Materiały źródłowe

• #1 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/

  Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. […] Currently, there is no effective treatment for this disease. […] This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods and modeling of this pathology in animals to evaluate the effectiveness of new therapies. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. […] Currently, there is no effective treatment for this disease. […] This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods and modeling of this pathology in animals to evaluate the effectiveness of new therapies. […] Early diagnosis is critically important. The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

• #3

• #4 Metachromatic leukodystrophy – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/metachromatic-leukodystrophy/diagnosis-treatment/drc-20354734

  Your doctor will perform a physical examination including a neurological exam and review symptoms and medical history to check for signs of metachromatic leukodystrophy. […] Your doctor may order tests to diagnose the disorder. These tests also help determine how severe the disorder is. […] Blood tests look for an enzyme deficiency that causes metachromatic leukodystrophy. Urine tests can be done to check sulfatide levels. […] Your doctor may conduct genetic tests for mutations in the gene associated with metachromatic leukodystrophy. He or she may also recommend testing family members, particularly women who are pregnant (prenatal testing), for mutations in the gene. […] This test measures electrical nerve impulses and function in muscles and nerves by passing a small current through electrodes on the skin. Your doctor may use this test to look for nerve damage (peripheral neuropathy), which is common in people with metachromatic leukodystrophy.

• #5 Metachromatic Leukodystrophy: What It Is, Causes & Symptoms

  https://my.clevelandclinic.org/health/diseases/6067-metachromatic-leukodystrophy

  If your or your childs healthcare provider (often, a neurologist) suspects metachromatic leukodystrophy based on your symptoms, theyll likely order these tests: […] Genetic testing: This can identify mutations in the ARSA and PSAP genes, which are responsible for MLD. […] Biochemical testing: This testing measures your levels of sulfatides. Tests include sulfatase enzyme activity and urine (pee) sulfatide levels. […] Brain MRI: A brain MRI can confirm the diagnosis of MLD. It can show the presence or absence of myelin, as theres a typical pattern of myelin loss in people who have MLD. […] You or your child will likely have additional testing if you receive an MLD diagnosis to see how the condition has affected your nervous system. These tests may include: […] Neurocognitive testing. […] Neuropsychological testing. […] Nerve conduction tests.

• #6 Metachromatic Leukodystrophy Workup: Laboratory Studies, Other Tests, Procedures

  https://emedicine.medscape.com/article/951840-workup

  Arylsulfatase A (ARSA) enzyme activity may be decreased in leukocytes or cultured skin fibroblasts. Cerebral spinal fluid (CSF) protein levels may be increased (although this finding is nonspecific). The range of values of ARSA activity in the CSF has been established empirically for metachromatic leukodystrophy (MLD) in clinical practice. […] Metachromatic leukodystrophy may be distinguished from ARSA pseudodeficiency using one of the following tests: […] Arylsulfatase A activity may be measured to identify carriers and make prenatal diagnoses. This test is available in a few select laboratories. In addition, multiplexed immune-quantification assays have been developed that screen numerous lysosomal proteins. Implementation of this technique in newborn screening (using blood spots) for early identification of lysosomal storage disorders has been shown to be feasible but requires further validation.

• #7 Metachromatic Leukodystrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560744/

  Metachromatic leukodystrophy is a rare lysosomal storage disease caused due to deficient activity of arylsulfatase A. […] Prompt diagnosis and treatment help in achieving a better quality of life. […] This activity describes the etiology, evaluation, and management of metachromatic leukodystrophy and highlights the role of the interprofessional team in evaluating and treating the patients with this condition. […] Describe the evaluation of metachromatic leukodystrophy. […] Arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts may be decreased. […] Metachromatic leukodystrophy must be distinguished from arylsulfatase A pseudo deficiency. […] A normal MRI does not exclude metachromatic leukodystrophy. […] The following tests can be conducted which could further help in diagnosing the case. […] Elevated cerebrospinal fluid protein concentrations may be helpful to arrive at the diagnosis. […] Metachromatic leukodystrophy is an autosomal recessive condition. […] Once the diagnosis is made, an interprofessional approach is vital.

• #8 Metachromatic Leukodystrophy (MLD) – United Leukodystrophy Foundation

  https://ulf.org/leukodystrophies/metachromatic-leukodystrophy-mld/

  How is MLD diagnosed? […] If a child displays some of the symptoms described previously, a series of biochemical evaluations and brain imaging studies can be performed. […] Because the most common cause of MLD is a deficiency of ASA, a blood sample or skin punch biopsy may be taken, and ASA activity can be measured; a low activity is suggestive of MLD. […] However, it should be noted that low ASA activity does not necessarily indicate MLD. […] Roughly 10% of the population carries this pseudodeficiency allele, so biochemical results should be interpreted in conjunction with other tests. […] Prenatal diagnosis for MLD is available. […] An MRI (Magnetic Resonance Imaging) may be performed to look for white matter disturbances characteristic of MLD.

• #9 Metachromatic Leukodystrophy (MLD) | LSDSS India

  https://lsdssindia.org/about-lysosomal-storage-disorders/metachromatic-leukodystrophy/

  Diagnosis involves genetic testing and enzyme activity assays, and while there is no cure, treatments like stem cell transplantation and supportive therapies aim to manage symptoms and slow disease progression. […] Diagnosing MLD involves several steps to confirm the presence of the disease and its underlying genetic cause: […] Initial assessment of symptoms, family history, and physical and neurological examination. […] Measuring the activity of the enzyme arylsulfatase A in blood or skin cells. Reduced activity indicates MLD. […] Detecting elevated levels of sulfatides in the urine, which are indicative of MLD. […] Identifying mutations in the ARSA gene through genetic testing. This confirms the diagnosis and helps differentiate MLD from other leukodystrophies. […] Genetic testing of family members to identify carriers of the ARSA mutation.

• #10 MED.00148 Gene Therapy for Metachromatic Leukodystrophy

  https://www.healthybluekansas.com/dam/medpolicies/healthyblueks/active/policies/PW_E003052.html

  MLD is typically diagnosed through a combination of clinical assessments, laboratory and imaging testing, and genetic testing (NORD, 2022; Shaimardanova, 2020). […] Genetic testing involves looking for mutations in the ARSA and PSAP genes (in rare cases, people with MLD have mutations in the PSAP gene). […] Biochemical diagnosis includes measurement of ARSA enzyme activity levels using samples from skin fibroblasts or leukocytes of individuals blood and urine, and measurement of urinary sulfatide levels using mass spectrometry. […] A diagnosis of MLD can be confirmed in individuals with progressive neurological dysfunction and/or leukodystrophy when there are all of the following: Biallelic ARSA pathogenic variants. […] Deficient levels of ARSA enzyme activity in leukocytes (typically ranging from less than 10 percent of normal to an undetectable level).

• #11 Invitae Metachromatic Leukodystrophy Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06174

  The Invitae Metachromatic Leukodystrophy Panel analyzes genes associated with metachromatic leukodystrophy. This test is indicated for any individual in whom a diagnosis of MLD is suspected based on clinical observation, neurologic findings that are consistent with progressive neurologic dysfunction, radiologic evidence of demyelination, or increased urinary sulfatide excretion. […] Additionally, any individual with low arylsulfatase A enzyme activity must undergo variant analysis for metachromatic leukodystrophy. […] The vast majority of cases of MLD are due to biallelic variants in ARSA. A very small percentage are due to pathogenic variants in PSAP, which encodes the Saposin-B (Sap-B) sphingolipid activator protein or Sulfatase-modifying factor-1 (SUMF1). Variants in SUMF1 cause multiple sulfatase deficiency. […] Based on validation study results, this assay achieves 99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions 15bp in length, and exon-level deletions and duplications.

• #12 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The next reliable method to monitor the disease course and the treatment effectiveness is to determine the ARSA enzyme activity. […] Magnetic resonance imaging is a very sensitive and highly informative method that allows early identification of white matter damage and evaluation of the disease. […] With MLD, the amount of sulfatides in the biological fluids of patients is increased, thus making possible to determine the level of sulfatides in plasma and urine using mass spectrometry. […] Nerve conduction studies (NCS) are also an important method for MLD diagnosis, which allow assessing the peripheral nervous system of patients, in particular the speed of nerve conduction and the amplitude of nerve action potential.

• #13 Metachromatic leukodystrophy – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/metachromatic-leukodystrophy/diagnosis-treatment/drc-20354734

  This test uses powerful magnets and radio waves to produce detailed pictures of the brain. These can identify a characteristic striped pattern (tigroid) of abnormal white matter (leukodystrophy) in the brain. […] Your doctor may assess psychological and thinking (cognitive) abilities and assess behavior. These tests may help determine how the condition affects brain function. Psychiatric and behavioral problems may be the first signs in juvenile and adult forms of metachromatic leukodystrophy.

• #14 Metachromatic Leukodystrophy | American Journal of Neuroradiology

  https://www.ajnr.org/ajnr-case-collections-diagnosis/metachromatic-leukodystrophy-0

  Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme arylsulfatase A, which is necessary for the normal metabolism of sulfatides (which are important constituents of the myelin sheath). […] Electromyography and nerve conduction velocity were abnormal in this patients case, with a demyelinating sensorimotor neuropathy pattern, and there were increased urine chromatography sulfatide levels. […] With T2WI, MLD manifests as symmetric, confluent areas of high signal intensity in the periventricular and deep white matter, with sparing of the subcortical U-fibers. No enhancement is evident at MR imaging. […] Tigroid and leopard patterns of demyelination, which suggest sparing of the perivascular white matter, can be seen in the periventricular white matter and centrum semiovale.

• #15 Leukodystrophy Imaging: Insights for Diagnostic Dilemmas

  https://www.mdpi.com/2076-3271/12/1/7

  As a demyelinating condition, MRI reveals brain demyelination and abnormalities in nerve conduction. Initial impact occurs in the central and periventricular white matter, progressing to subcortical structures. Extreme cases may exhibit projection fiber involvement, leading to distinctive patterns like the “tigroid pattern” and “leopard skin” pattern. Nearly all patients with metachromatic leukodystrophy show splenial corpus callosum demyelination. T2-weighted FLAIR images display symmetric, confluent hyperintense areas in the periventricular white matter, consistent with the demyelinating nature of the disorder. Lastly, MRI modalities, including diffusion-weighted parameters, demyelination load, and MR spectroscopy, hold potential in aiding early diagnosis by providing insights into nonspecific white matter changes associated with metachromatic leukodystrophy.

• #16 Metachromatic leukodystrophy | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/metachromatic-leukodystrophy?lang=us

  Metachromatic leukodystrophy (MLD) is the most common hereditary (autosomal recessive) leukodystrophy and is one of the lysosomal storage disorders. It has characteristic imaging features including peri-atrial and to a lesser extent frontal horns leukodystrophy as well as periventricular perivenular sparing results in „tigroid pattern” on fluid-sensitive MRI sequences. […] Management is generally supportive in nature. Emerging therapies include gene therapies such as atidarsagene autotemcel, which has been shown to reduce risk of severe motor impairment. […] Krabbe disease is one of the main differential diagnoses both clinically and by imaging.

• #17 Metachromatic leukodystrophy – Wikipedia

  https://en.wikipedia.org/wiki/Metachromatic_leukodystrophy

  Clinical examination and MRI are often the first steps in an MLD diagnosis. MRI can be indicative of MLD but is not adequate as a confirming test. An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD. Urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results. Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted. […] MLD Foundation formally launched a newborn screening initiative in late 2017. The screen development started in the early 2010s at the University of Washington, by Professor Michael H. Gelb. A deidentified pilot study was launched in April 2016 in Washington state. Positive results led to MLD being included in the ScreenPlus identified baby research project in New York state, which is currently scheduled to launch in Q1’2021.

• #18 Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02518-z

  Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). […] Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. […] This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis. […] Upon suspicion of disease, genetic analysis for ARSA and PSAP mutations, brain imaging, and biochemical testing of ARSA enzymatic activity are used in the diagnosis of MLD. […] MRI is typically the first step in directing clinicians to conduct biochemical and genetic testing, which can ultimately lead to a definitive diagnosis.

• #19 Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7606900/

  The next reliable method to monitor the disease course and the treatment effectiveness is to determine the ARSA enzyme activity. […] Magnetic resonance imaging is a very sensitive and highly informative method that allows early identification of white matter damage and evaluation of the disease. […] With MLD, the amount of sulfatides in the biological fluids of patients is increased, thus making possible to determine the level of sulfatides in plasma and urine using mass spectrometry. […] Nerve conduction studies (NCS) are also an important method for MLD diagnosis, which allow assessing the peripheral nervous system of patients, in particular the speed of nerve conduction and the amplitude of nerve action potential. […] As MDL is characterized by different clinical manifestations, effective modeling of the disease is important to study the genetic basis of the disease, disease progression, diagnosis, and therapy.

• #20 What Is Metachromatic Leukodystrophy?

  https://www.icliniq.com/articles/neurological-health/metachromatic-leukodystrophy

  Nerve conduction study (NCS): In this study, two electrodes are attached to the skin; one stimulates the nerves, and the other measures the response from the nerve. It helps measure the movement of impulses within the nerve and evaluate any nerve damage. […] Molecular genetic testing is a confirmatory test. It helps in determining the mutation in genes that causes metachromatic leukodystrophy. […] A neurocognitive test determines memory loss, decreased motor function, and impulsiveness in juvenile and adult forms of MLD.

• #21 What Is Metachromatic Leukodystrophy?

  https://www.icliniq.com/articles/neurological-health/metachromatic-leukodystrophy

  Metachromatic leukodystrophy (MLD) affects one in 40,000 to one in 160,000 individuals. […] How Is Metachromatic Leukodystrophy Diagnosed? […] A blood examination is ordered to detect the deficiency of arylsulfatase A enzyme due to mutation in the ARSA gene. […] A urine test helps detect abnormal levels of certain substances excreted in the urine. In metachromatic leukodystrophy, levels of sulfatides are checked in the urine samples. […] Magnetic resonance imaging (MRI) detects any lesion, cyst, or tumor in the brain and spinal cord. The MRI of metachromatic leukodystrophy shows the classical striped pattern of white matter in the brain and the destruction of the myelin sheath. […] A lumbar puncture involves the removal of a sample of cerebrospinal fluid (CSF) from the lower back region surrounding the brain and spinal cord to diagnose various neurological conditions. The CSF shows elevated proteins in metachromatic leukodystrophy.

• #22 Metachromatic leukodystrophy. Case presentation☆

  https://www.redalyc.org/journal/806/80651120007/html/

  MLD is suspected when metachromatic granules are found in biopsy of the conjunctiva or sural nerve. Diagnosis is confirmed when low ARSA activity is documented in leukocytes or fibroblast culture. […] The diagnosis is based on analysis of mutations, biochemistry tests and clinical assessments. […] The tests that can be used for the diagnosis of MLD include the following: Blood or skin tests for low ARSA activity, Brain MRI, Lumbar puncture to test for high protein concentrations, Urinalysis for high sulfatide concentrations, Nerve conduction velocity studies. […] In ARSA pseudo-deficiency, there is a partial deficit that does not cause clinical disorders, and this can complicate the diagnosis and identification of patients with MLD. […] Sulfatide in nerve and cerebrospinal fluid and lysosulfatide accumulation are markers of severity in peripheral nerve only; they do not reflect the extent of the damage in the central nervous system.

• #23 Metachromatic leukodystrophy. Case presentation☆

  https://www.redalyc.org/journal/806/80651120007/html/

  Before birth, ARSA activity can be determined by cell culture of amniotic fluid or chorionic villi. Prenatal diagnosis is indicated for couples who have a history of an affected child. […] The radiological changes in MLD can be distinguished from microangiopathy related to ageing or multiple sclerosis, because the lesions in the white matter tend to be symmetrical and confluent. […] The behavioural changes associated with subtle symptoms of memory deficit and motor alterations can suggest the diagnosis of early-onset dementia. […] In adolescents, MLD can resemble a psychosis because the disease alters the critical process of myelination, especially in the frontotemporal anatomical connections. […] MRI findings include hyperintense areas of diffuse, bilateral, and often symmetrical demyelination in the periventricular white matter and cerebellum that may converge with disease progression, with frontal predominance in the late stages (juvenile forms and in adults).

• #24 Metachromatic leukodystrophy: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001205.htm

  Metachromatic leukodystrophy (MLD) is a genetic disorder that affects nerves, muscles, other organs, and behavior. It slowly gets worse over time. […] Your health care provider will perform a physical exam, focusing on the nervous system symptoms. […] Tests that may be done include: Blood or skin culture to look for low arylsulfatase A activity, Blood test to look for low arylsulfatase A enzyme levels, DNA testing for the ARSA gene, MRI of the brain, Nerve biopsy, Nerve signaling studies, Urinalysis. […] Genetic counseling is recommended if you have a family history of this disorder.

• #25 Metachromatic Leukodystrophy Workup: Laboratory Studies, Other Tests, Procedures

  https://emedicine.medscape.com/article/951840-workup

  Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of metachromatic leukodystrophy but is nonspecific. […] Metachromatic granules are found in biopsy specimens from peripheral nerves, the kidney, or the gallbladder. Widespread loss of myelin in the CNS and peripheral nerves may be present. […] The following tests may be indicated:

• #26 MED.00148 Gene Therapy for Metachromatic Leukodystrophy

  https://www.healthybluekansas.com/dam/medpolicies/healthyblueks/active/policies/PW_E003052.html

  Elevated levels of sulfatides in urine. […] Other diagnostic tests include ultrasound to detect an increase in peripheral nerves. […] Magnetic resonance imaging (MRI) of the brain can help confirm a diagnosis of MLD by showing the presence and absence of myelin; individuals with MLD have a distinctive pattern of myelin loss in the brain.

• #27 Leukodystrophy Imaging: Insights for Diagnostic Dilemmas

  https://www.mdpi.com/2076-3271/12/1/7

  Metachromatic leukodystrophy, an autosomal recessive lysosomal storage disease, is characterized by a deficiency of arylsulfatase A (ARSA) due to a mutation in the arylsulfatase A gene on chromosome 22q13.3-qter. ARSA plays a crucial role in the degradation of sulphatide, a membrane lipid found in myelin, the distal tubules of the kidney, and bile duct epithelia. The deficiency of ARSA leads to the accumulation of sulphatide primarily affecting the nervous system and resulting in progressive demyelination, presenting clinically with ataxia, optic atrophy, dementia, and decerebrate posturing. […] Children suspected of metachromatic leukodystrophy often exhibit delays in meeting developmental milestones and a decline in both gross and fine motor skills. Diagnosis involves laboratory studies to assess ARSA levels, with criteria ranging from undetectable to less than 10% of the normal value. Distinguishing metachromatic leukodystrophy from arylsulfatase A pseudodeficiency, present in about 1% of the general population, requires additional assessments such as urine sulfatide levels, radiolabeled sulfatide fibroblast loading, and DNA analysis.

• #28 Metachromatic leukodystrophy. Case presentation | Revista Colombiana de Psiquiatría (English Edition)

  https://www.elsevier.es/en-revista-revista-colombiana-psiquiatria-english-edition–479-articulo-metachromatic-leukodystrophy-case-presentation-S2530312017300036

  Metachromatic leukodystrophy (MLD) is a rare demyelinating disease (prevalence 1:40,000), also called arylsulfatase A deficiency (ARS-A), which may present with neurological and psychiatric symptoms. Clinical assessment may be difficult, due to unspecific signs and symptoms. […] MLD is suspected when metachromatic granules are found in biopsy of the conjunctiva or sural nerve. Diagnosis is confirmed when low ARSA activity is documented in leukocytes or fibroblast culture. […] The diagnosis is based on analysis of mutations, biochemistry tests and clinical assessments. […] The tests that can be used for the diagnosis of MLD include the following: Blood or skin tests for low ARSA activity. Brain MRI. Lumbar puncture to test for high protein concentrations. Urinalysis for high sulfatide concentrations. Nerve conduction velocity studies. […] In ARSA pseudo-deficiency, there is a partial deficit that does not cause clinical disorders, and this can complicate the diagnosis and identification of patients with MLD. This condition can also be found in healthy subjects.

• #29

  https://omim.org/entry/250100

  A number sign (#) is used with this entry because metachromatic leukodystrophy (MLD) is caused by homozygous or compound heterozygous mutation in the arylsulfatase A gene (ARSA; 607574) on chromosome 22q13. […] Austin et al. (1964) determined that the defect concerns the lysosomal enzyme arylsulfatase A. Austin’s test to demonstrate absence of arylsulfatase A activity in the urine was useful in early diagnosis (Greene et al., 1967). Kaback and Howell (1970) demonstrated profound deficiency of arylsulfatase A in cultured skin fibroblasts of patients and an intermediate deficiency in carriers. Normally enzyme levels are low in midtrimester amniotic cells; hence, homozygotes cannot be reliably identified by amniocentesis. […] Poenaru et al. (1988) described a method of first-trimester prenatal diagnosis of metachromatic leukodystrophy using immunoprecipitation-electrophoresis on chorionic villus material. […] Baldinger et al. (1987) discussed the complications of genetic counseling and prenatal diagnosis resulting from the occurrence of the pseudodeficiency phenotype.

• #30 Metachromatic Leukodystrophy |

  https://www.huntershope.org/family-care/leukodystrophies/metachromatic-leukodystrophy/

  A proper diagnosis is a confirmation of the deficiency of the missing enzyme and the resulting lowered Arylsulfatase-A (ARSA) activity in the body. This diagnosis is confirmed and validated by a number of procedures, with the more common procedures including blood testing, urine testing and imaging studies. […] Unfortunately, MLD is often misdiagnosed, sometimes several times before the correct diagnosis is made. Common misdiagnoses for MLD include Cerebral Palsy, Batten’s Disease, and ADHD – especially with children. In adults, since the presentation is often first psychological not physical, it can be misdiagnosed as a variety of psychological conditions. […] Newborn screening for MLD is currently being validated in a medium-scale pilot study by University of Washington investigators. This would help in early detection of more individuals with MLD who could potentially benefit from transplant.

• #31 CALD and MLD

  https://patienteducation.asgct.org/disease-treatments/leukodystrophy

  LENMELDY is an FDA-approved gene therapy for infants and children with metachromatic leukodystrophy (MLD) who have not yet exhibited symptoms and children with early stage MLD. […] Genetic testing can detect mutations or variations in the genes that can cause these disorders. Parents can consider requesting genetic testing before or during pregnancy to determine if the child is at risk. […] Early diagnosis for ALD can be made through screenings completed for newborns. Although an increasing number of U.S. states have recently been adding ALD to their standard newborn screening panels, there are still many which do not. […] For MLD to be added to the Recommended Uniform Screening Panel (RUSP). This is a list of disorders that the Secretary of the Department of Health and Human Services (HHS) recommends for states to screen as part of their newborn screening panel.

• #32 MLD Foundation

  https://mld.foundation/

  If you or your loved one is newly diagnosed, or you suspect MLD, please visit our What Do I Do Next? page for a step-by-step guide on how to expedite a diagnostic confirmation, next steps to access therapy, and more. We can and want to help! […] Metachromatic Leukodystrophy (MLD) is a progressive, genetic, neurometabolic disease that affects the nervous system due to the lack of an enzyme, Ayrlsulfatase-A (ARSA.) Over 300 variants of the ARSA gene on Chromosome 22 are known to cause MLD. […] While there is now an FDA-approved gene therapy available for pre-symptomatic infantile and early juveniles, Lenmeldy, access for early-symptomatic cases, older patient cases is much more limited or non-existent. […] The MLD Foundation supports and empowers families living with Metachromatic Leukodystrophy through community and compassion for families, increasing awareness, influencing and funding research, and promoting education. […] MLD Foundation works on behalf of patients and families to increase awareness of MLD and advocate for newborn screening and treatments at the state and federal levels. […] We work alongside researchers, pharmaceutical companies, clinicians and more in efforts to treat and cure MLD.

• #33 Metachromatic leukodystrophy – UF Health

  https://ufhealth.org/conditions-and-treatments/metachromatic-leukodystrophy

  Leukodystrophies are a rare group of inherited diseases that affect the white matter of the brain and spinal cord. […] The suspected diagnosis starts with a brain Magnetic Resonance Imaging (MRI). However, the definitive diagnosis will be done through a detailed interpretation of the brain MRI images, clinical findings, and different a comprehensive metabolic or genetic panel of tests. […] It is not uncommon that patients can be misdiagnosed with multiple neurological disorders as the initial problems can overlap with other more common conditions.

• #34 Understanding caregiver descriptions of initial signs and symptoms to improve diagnosis of metachromatic leukodystrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02518-z

  Therefore, these clinical tests are not initiated until MLD is suspected, which can lead to significant delays in biochemical testing due to the often non-specific nature of initial signs of MLD. […] Early recognition of MLD is crucial to increase the chance of individuals with MLD qualifying for and benefiting from therapy. […] The goal of this paper is to offer insight into the caregiver descriptions of the initial symptomatology of MLD and ultimately to improve communication between clinicians and families impacted by this condition. […] This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. […] The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD. […] The findings from this study offer insight into caregivers experiences and observations that can be used to raise the index of suspicion to trigger earlier investigations into MLD, furthering the objective to eradicate this diagnostic odyssey in MLD.

• #35 About MLD Metachromatic Leukodystrophy | MLD Support Association UK

  https://www.mldsupportuk.org.uk/about-mld/

  MLD is directly caused by a deficiency of the enzyme Arylsulfatase-A. […] However, with modern diagnostic tools such as MRI Scans and genetic sequencing, it means that there are fewer incorrect diagnoses and it is possible that the incidence may prove to be higher. […] Unfortunately, as MLD is such a rare disease and health professionals generally see less than one or two cases in their career, these children are frequently diagnosed as cerebral palsy as they initially have problems with walking and toe walking. […] As time goes by, limbs can become painful as contractures develop. […] Unfortunately, this delay often means that any treatment so far available becomes impossible as the symptoms are too far advanced. […] Again, unfortunately, this is normally initially misdiagnosed as a psychiatric illness, frequently schizophrenia and medication is given which, generally, exacerbates the problems. […] Many clinicians believe that Adult-Onset MLD is currently much under-diagnosed. […] Early diagnosis is the key here.

• #36

  https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/07000/metachromatic_leukodystrophy_in_infant_presenting.55.aspx

  In most cases, MLD is not included in the fetus and newborn genetic screening tests given that MLD is a rare disease. […] However, early diagnosis is critically important. The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Early diagnosis plays a pivotal role in managing MLD. […] This underscores the importance of considering rare diseases in cases of unexplained neurological regression in children. […] This case report also delineates severe metabolic acidosis, likely stemming from MLD. […] Regrettably, this case highlights the dearth of effective treatments for MLD. […] Despite these efforts, the infant’s condition continued to deteriorate alarmingly.

• #37 Orphanet: Metachromatic leukodystrophy

  https://www.orpha.net/en/disease/detail/512

  A rare lysosomal disease characterized by accumulation of sulfatides in the central and peripheral nervous system due to deficiency of the enzyme arylsulfatase A, leading to demyelination. […] Three clinical subtypes can be distinguished based on the age of onset: late infantile, juvenile, and adult. […] Lead symptoms are deterioration in motor or cognitive function or behavioral problems, depending on the subtype, all eventually culminating in a decerebrated state and death after a highly variable disease course and duration. […] Mode of inheritance is autosomal recessive. […] Diagnostic tests (106)

• #38 Metachromatic Leukodystrophy | Kennedy Krieger Institute

  https://www.kennedykrieger.org/patient-care/conditions/leukodystrophy/metachromatic-leukodystrophy

  Metachromatic leukodystrophy (MLD) is a rare autosomal recessive leukodystrophy, which means both copies of the affected gene in each cell have mutations. […] There are late infantile, juvenile, and adult forms. About 75 percent of patients have the late infantile or juvenile forms equally divided between them. Twenty-five percent have the adult form. […] The late infantile form manifests between 6 months and 4 years of age, and starts with unsteady gait and gradual loss of the ability to walk, and mental decline. […] In the juvenile form, the age of onset ranges from 4 to 16 years. Patients show gradual deterioration in school performance, slurred speech, clumsy gait, and incontinence. […] Onset of the adult form of MLD has been reported at various ages up to the sixties. Patients show a gradual decline of intellectual abilities.

• #39 A systematic review on the birth prevalence of metachromatic leukodystrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03044-w

  The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. […] This review provides a foundation for further analysis of the regional epidemiology of MLD. […] The objective of this systematic review was to generate a qualitative synthesis of estimates of incidence, birth prevalence and prevalence of MLD in countries across the world, stratifying results by clinical subtype. […] For the purpose of this systematic review, birth prevalence was defined as the number of new cases of MLD diagnosed over a given time period divided by the number of live births within the same time period (also referred to as the lifetime risk of MLD at birth).

• #40 Metachromatic leukodystrophy. Case presentation☆

  https://www.redalyc.org/journal/806/80651120007/html/

  MRI is more sensitive than CT in the detection of lesions in the white matter and it is useful for visualising early-onset lesions in regions of the posterior fossa (brain stem or cerebellum); it also shows the severity and extent of the disease. […] The diagnosis was made with the participation of psychiatry, neurology and genetics departments. […] Psychiatrists should be aware of their role in early diagnosis of MLD, since initial symptoms may lead to psychiatric consultation.

• #41 Family

  https://patents.google.com/patent/EP2743700A1/en

  The present invention is related to a method for diagnosing metachromatic leukodystrophy, a method for determining the effectiveness of at least one treatment applied to a subject being positively tested for suffering from or being at risk of suffering from metachromatic leukodystrophy, a method for determining the effectiveness of a compound for the treatment of metachromatic leukodystrophy, the use of mass spectrometric analysis for the detection of a biomarker, and a kit for determining the presence of a biomarker in a sample from a subject. […] To date a definitive diagnosis of MLD can only be made by measurement of ARSA activity on leukocytes together with genetic confirmation. […] Therefore, the identification of biomarkers for the early detection and diagnosis of MLD holds great promise to improve the clinical outcome of patients. It is especially important for patients with vague or no symptoms or to detect patients which fail to respond to a therapy.

• #42 Family

  https://patents.google.com/patent/EP2743700A1/en

  A biomarker should be technically feasible in many hands, easy to measure; useful, with a consistent, relative magnitude between affected and controls, or treated and untreated; reliable, and accurate clinically, and classifiable as strongly predictive or prognostic. […] Today, no biomarker for diagnosing MLD is available. […] The present inventors have surprisingly found that free lyso-Gb1-sulfatide, also referred to herein preferably as free lyso-glycocerebroside-sulfatide, constitutes a biomarker which allows for a method for diagnosing MLD in a subject, more specifically diagnosing MLD in a subject with high specificity and sensitivity using said free lyso-Gb1-sulfatide as the biomarker. […] The present inventors have also surprisingly found that free lyso-Gb1-sulfatide, which can be detected by the methods of the present invention, is circulating in the blood of a subject in a concentration of approximately 1/1000 of total Gb1-sulfatide.

• #43 Family

  https://patents.google.com/patent/EP2743700A1/en

  The term „level” or „level of a biomarker” as used herein, preferably means the concentration of a substance and/or titer of a substance, preferably of a biomarker of the invention and more preferably of free lyso-Gb1-sulfatide, within a sample of a subject. […] The level of a biomarker is different between different statuses of MLD if the mean or median level of the biomarker in the different groups is calculated to be statistically significant. […] The term „determining the level” of a biomarker as used herein, preferably means methods which include quantifying an amount of at least one substance in a sample from a subject and/or quantifying an amount of said substance contained in a part of the body of the subject, such as saliva, blood, lymph, serum, plasma or liquor and/or quantifying an amount of said substance in the subject, the substance being selected from the group comprising a biomarker.

• #44 Family

  https://patents.google.com/patent/EP2743700A1/en

  It is thus an embodiment of the present invention that the method for diagnosing MLD in a subject according to the present invention may be applied every 3 months and levels of the biomarker thus determined will be compared in order to determine the effectiveness of the treatment(s) and/or therapy/therapies applied to the subject. […] The present invention provides methods for the diagnosis of MLD and biomarkers used in said methods which allow the diagnosis of MLD with high sensitivity and high specificity.

• #45

  https://journals.lww.com/annals-of-medicine-and-surgery/fulltext/2024/07000/metachromatic_leukodystrophy_in_infant_presenting.55.aspx

  Managing a case like these demand a multidisciplinary approach involving pediatricians, neurologists, radiologists, and intensive care specialists. […] This case report is a poignant illustration of the challenges of rare genetic diseases like MLD. It emphasizes the need for early diagnosis, genetic testing, and a multidisciplinary approach to managing these devastating conditions.

• #46 Metachromatic leukodystrophy Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/metachromatic-leukodystrophy

  Metachromatic leukodystrophy (MLD) is a genetic disorder that affects nerves, muscles, other organs, and behavior. It slowly gets worse over time. […] Your health care provider will perform a physical exam, focusing on the nervous system symptoms. […] Tests that may be done include: Blood or skin culture to look for low arylsulfatase A activity, Blood test to look for low arylsulfatase A enzyme levels, DNA testing for the ARSA gene, MRI of the brain, Nerve biopsy, Nerve signaling studies, Urinalysis. […] There is no cure for MLD. Care focuses on treating the symptoms and preserving the person’s quality of life with physical and occupational therapy. […] Genetic counseling is recommended if you have a family history of this disorder.

• #47 Metachromatic Leukodystrophy: A Scoring System for Brain MR Imaging Observations | American Journal of Neuroradiology

  https://www.ajnr.org/content/30/10/1893

  Metachromatic leukodystrophy (MLD) is a devastating demyelinating disease for which novel therapies are being tested. […] We hypothesized that MR imaging of brain lesion involvement in MLD could be quantified along a scale. […] The MLD MR severity scoring method can be used to provide a measure of brain MR imaging involvement in MLD patients. […] To date, there is no adequate quantitative measure of MR imaging brain involvement in patients with MLD to correlate with ongoing diagnostic and therapeutic research. […] The purpose of our study was to adapt the previously developed ALD scoring system to reliably measure MR imaging brain involvement in patients with MLD. […] We hypothesized that the range of MR imaging of brain lesion involvement in MLD could be quantified along a scale.

• #48 Metachromatic Leukodystrophy: A Scoring System for Brain MR Imaging Observations | American Journal of Neuroradiology

  https://www.ajnr.org/content/30/10/1893

  We demonstrated that the MLD MR imaging severity scoring method can be used to provide a measure of brain MR imaging involvement across different age groups and subtypes of MLD. […] When used in conjunction with clinical parameters, the MLD MR imaging severity score may help to better define the natural history of MLD and may be useful in monitoring the response to developing therapies.

• #49 MLD – Metachromatic Leukodystrophy – Alex – The Leukodystrophy Charity

  https://alextlc.org/condition/metachromatic-leukodystrophy-mld/

  Metachromatic Leukodystrophy (MLD) is a rare lysosomal storage disorder caused by deficient activity of the enzyme arylsulfatase A. […] Gene therapy is available in the UK and USA for treating MLD, please consult your specialist doctor for more information. […] Genetic counselling is essential for affected families due to the inheritance pattern of the condition. This is available at hospitals and Regional Genetic Centres. Please contact your doctor if you have any questions. […] Gene therapy is available in the UK for patients with Early Juvenile/Late infantile MLD through the NHS, the drug is known as Libmeldy. It is also available in the USA and known as Lenmeldy. Please consult your specialist doctor for more information.

• #50 MLD Learning Zone | Metachromatic Leukodystrophy in Pediatrics

  https://mld.spot-early-signs.org/mlds4m2-understanding_the_diagnostic_journey_of_patients

  MLD is a rare neurodegenerative disorder where every day counts. […] Through the Think Rare Program, we equip frontline healthcare professionals with the insights and tools to spot these early indicators, intervene sooner, and ultimately change the course of a child’s life. […] Access our growing library of expert presentations, clinical case discussions, and diagnostic guidance on MLD. […] Early Diagnosis Of Metachromatic Leukodystrophy (MLD): Understanding The Diagnostic Journey Of Patients […] Successfully Spotting The Early Signs Of Metachromatic Leukodystrophy (MLD) […] Metachromatic Leukodystrophy (MLD) Screening Update – Pre-Symptomatic Identification. […] Our international faculty comprises leading clinicians and researchers committed to transforming the MLD diagnostic journey.

• #51 SciELO Brazil – Metachromatic leukodystrophy: pediatric presentation and the challenges of early diagnosis Metachromatic leukodystrophy: pediatric presentation and the challenges of early diagnosis

  https://www.scielo.br/j/ramb/a/4Tcf3mYwRfLMdxkTzwXxT5q/

  Even though there is still no curative treatment for this disease, new therapeutic possibilities are emerging, such as intrathecal enzyme replacement and hematopoietic stem-cell transplantation (HSCT) associated with gene therapy. […] In short, Metachromatic Leukodystrophy is a rare, devastating, and progressive hereditary disease. Given the possibility of emerging treatments specific to this illness, it is vital to obtain an early diagnosis.

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