Lysosomal storage diseases (LSDs) are a group of hereditary disorders that disrupt lysosomal function, specifically, enzymes involved in cell metabolism, signaling, substrate processing, innate immunity, apoptosis, and other complex cell recycling processes. This process is extremely complex. The accumulation of undigested or partially processed molecules become toxic for the host cell. The onset tends to predominate in early infancy or childhood, with some disease onset in adulthood. LSDs tend to have a progressive neurodegenerative course and can cause multi-organ failure and, ultimately, death.
Leukodystrophies are inherited disorders that predominantly affect the central nervous system (CNS) white matter tracts, and it's cellular components. These may include glial cells, myelin sheath, and axons. Genetic leukodystrophies tend to combine features of leukodystrophies with development issues caused by inborn errors of metabolism, disorders of DNA transcription, translation, production of critical CNS proteins including myelin, and neuronal cytoskeletal dysfunction.
Metachromatic leukodystrophy is a demyelinating, autosomal recessive genetic leukodystrophy and LSD, caused by an inborn error of metabolism in the arylsulfatase A lysosomal enzyme. This leads to the accumulation of sulfatides, which result in the dysfunction and destruction of the CNS/PNS myelin sheaths. It also accumulates in other organs, including the kidneys, testes, and gallbladder. It can be classified based on the age of onset and clinical features of the disease. All forms of the disease involve a progressive deterioration of neurodevelopment and neurocognitive function.
Metachromatic leukodystrophy is caused by deficient activity of arylsulfatase A. In almost all cases, mutations are in the arylsulfatase A gene (ARSA gene), on chromosome 22q13.3-qter. Two alleles, A and I have contributed to approximately 50 percent of cases and are responsible for different clinical expression of the disease. In some cases, it is due to the deficiency of sphingolipid activator protein SAP-B (saposin B), which is responsible for the degradation of sulfatides by ARSA. This form is caused by mutations in the prosaposin gene (PSAP gene).
The prevalence of metachromatic leukodystrophy ranges from 1/40,000 to 1/100,000 in the northern European and North American populations. Incidence is estimated to be 1/40,000 births in the United States of America. There is no sexual and racial predilection. The disease is categorized based on the age of onset.
Metachromatic leukodystrophy is a lysosomal storage disease characterized by the inability to degrade sulfated glycolipids, mainly the galactosyl-3-sulfate ceramides. It is caused by deficient activity of lysosomal enzyme arylsulfatase A, most commonly due to mutations in the arylsulfatase A (ARSA gene). During the process, the sulfated glycolipids are degraded into galactocerebroside by the enzyme Arylsulfatase A.
Metachromatic granules may be seen in the tissue specimen. In the nervous system, the loss of myelinated oligodendrocytes is seen.
Leukodystrophies are generally suspected in pediatric patients with difficulties in meeting appropriate development milestones when previously was able to do so. Peripheral neuropathy can present prior to dysarthria and other CNS manifestations. A decline in gross and fine motor skills at any age should be evaluated for metachromatic leukodystrophy. Clinical manifestations of the diseases can be categorized by the age at which the disease onset.
Arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts may be decreased. Values generally range from undetectable to less than 10 percent of the normal values. However, Metachromatic Leukodystrophy must be distinguished from arylsulfatase A pseudo deficiency (present in approximately one percent of the general population). Patients with arylsulfatase A pseudo deficiency has arylsulfatase A levels ranging from 5% to 20% of normal values without clinical or radiographic disease. The followings tests can be used to differentiate them:
Brain MRI shows T2-weighted FLAIR symmetric and confluent hyperintensities diffusely on the frontal and parietal periventricular white matter, which are characteristic of the diseases but nonspecific. T1-weighted images tend to be hypointense, given it is a demyelinating disorder. A normal MRI does not exclude metachromatic leukodystrophy.
Ultrasound or CT abdomen may reveal hyperplastic gallbladder polyps, which can predispose for gallbladder carcinoma.
The following tests can be conducted with could further help in diagnosing the case.
No curative treatment options are currently available for this disease—the focus in the enhancement of the quality of life by focusing on symptom management. Symptomatic supportive care is needed to address to neurocognitive and neuropsychiatric disturbances, seizures, dystonias, spasticity, feeding problems, and constipation.
MLD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member.
Experimental and emerging therapies:
Hence, preliminary evidence suggests that gene therapy and hematopoietic stem cell transplantation combined with gene therapy are promising treatment options. However, the cellular pathogenesis of metachromatic leukodystrophy is complex. Several other LSDs have used disease-specific gene and enzyme replacement therapies with some success. Small-molecule therapies are emergent therapy for some LSDs. Although gene therapy and genome microRNA editing are at advanced preclinical stages, there is a need for phase III/IV clinical trials.
Metachromatic leukodystrophy must be differentiated from other LSDs with similar presentation and with arylsulfatase A pseudodeficiency. Arylsulfatase A pseudodeficiency can be differentiated using gene mutation analysis or evaluation of radiolabeled sulfatide fibroblast uptake and accumulation. Other differentials that must be kept in mind while diagnosing metachromatic leukodystrophy are:
Metachromatic leukodystrophy is a progressive disease. This means that the symptoms tend to get worse over time. People who have this disease lose all muscle and mental functions eventually. Lifespan often depends on the age at which a person is first diagnosed.
Therapies focus on the quality of life, and functional activities of daily living can help in areas of mobility, cognition, communication, and oral intake. Safety measures are to avoid falls at home. The most common complications of the disease include:
Regular consultations with followings specialists are generally needed:
Patients often find it difficult to carry out activities of daily living as the condition worsens. Patients and family members should be properly counseled about the progressive nature of the disease and the prognosis. Some of the related complications and co-morbidities are gastroesophageal reflux, constipation, dental caries, impaired vision, among others. Pharmacological management, physical therapies, and family support can help prevent further decline of the patient and improve quality of life.
Metachromatic leukodystrophy is an autosomal recessive condition. Parents require counseling about the inheritance pattern of the condition if the family has a positive family history of the condition.
Metachromatic leukodystrophy is an autosomal recessive lysosomal disorder that results in a buildup of sulfatides that leads to the destruction of the myelin sheath, leading to progressive demyelination of the central and peripheral nervous system. Once the diagnosis is made, an interprofessional approach is vital.
Medical centers with specialty teams can offer information about the disorder, coordinate care among specialists, help evaluate options, and provide treatment. Primary care physicians, neurology physicians, pathologists, radiologists, physiotherapists, among others, can form a collaborative team for the best possible outcome. A physical therapist, occupational therapist, orthopedist, ophthalmologist, neuropsychologist, and other specialists may be involved are often needed for long term follow up and evaluation. Working with a nutrition specialist (dietitian) can help provide proper nutrition. Eventually, it may become difficult to swallow food or liquid. This may require assistive feeding devices as the condition progresses.
The role of the nurse in education is indispensable. The patient and the family need to know about the course of the disease, lifestyle modifications, and the need to follow up. The physical and occupational therapist should be consulted to assist with ambulation, use of an ambulatory device, and how to perform daily living activities. Couples with a family history of the disease should be offered genetic counseling during pregnancy.
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