Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease consisting of progressive demyelination of the peripheral and central nervous systems. In most patients, it is attributed to a mutation in the arylsulfatase A (ARSA) gene, which in turn hinders the production of arysulfatase A. This enzyme is necessary for the desulfation of cerebroside, a glycolipid of myelin.
There are three subtypes of metachromatic leukodystrophy. The clinical presentation is dependent on the subtype.
- Late-infantile metachromatic leukodystrophy typically onsets between 6 months to 2 years of age. Common presenting symptoms are a weakness, ataxia, frequent falls, toe walking, clumsiness, hypotonia, and slurred speech  . Symptoms that appear with the progressive disease include impaired speech, inability to stand, increased muscle tone, seizures, impaired eyesight due to optic atrophy, impaired hearing, cognitive impairment, and peripheral neuropathy. End stage disease symptoms include decerebrate posturing, tonic spasms, and severe cognitive impairment . Death usually occurs by five years of age.
- Juvenile metachromatic leukodystrophy commonly occurs between 3 and 16 years of age. The initial presentation includes behavioral problems, intellectual impairment, gait disturbance, incontinence, and peripheral neuropathy . Seizures occur with the advanced disease. Progression to death occurs about six years after the onset of symptoms .
- Adult metachromatic leukodystrophy generally presents at 17 years of age or older. Patients often present with dementia, behavioral problems, peripheral neuropathy, seizures, and less commonly, optic atrophy and psychiatric manifestations (e.g., personality changes, schizophrenia, dementia)  . Symptoms may wax and wane over several decades but are progressive overall  .
Entire Body System
- Difficulty Walking
Metachromatic leukodystrophy Pathology Type Genetic Cause(s) Inheriting faulty gene from both parents Symptoms Difficulty walking, muscle wasting and weakness, appearance of mental illness Mortality Rate Inevitably fatal Treatments None Show Information [house.wikia.com]
Some psychiatric disorders coupled with difficulty walking or muscle wasting suggests the possibility of MLD. Blood testing can show a reduced activity of the ARSA enzyme. [secure.ssa.gov]
Initial symptoms include trouble in school, behavioral problems, clumsiness, difficulty walking normally, slurred speech, and seizures. Life expectancy ranges from the teenage years to the 30s. Adult: Symptoms may begin at any point after puberty. [sema4genomics.com]
Before the age of 2, however, these children may develop difficulty walking, muscle wasting, weakness, developmental delay, and vision loss. [thinkgenetic.com]
In the late-infantile form, which is the most common form of MLD (50-60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. [mldsupportuk.org.uk]
- Problems at School
Initial symptoms are variable, but include worsening problems with school or work performance and personality changes. [thinkgenetic.com]
In the juvenile form, the initial symptoms are usually declining school performance and the onset of behavioral problems. Clumsiness, gait problems, slurred speech, incontinence, bizarre behavior and seizures are also observed. [genedx.com]
Initial manifestations include decline in school performance and emergence of behavioral problems, followed by clumsiness, gait problems, slurred speech, incontinence, and bizarre behaviors. Seizures may occur. [flipper.diff.org]
- Muscle Spasm
Other symptoms can also include vision problems leading to blindness, personality changes, and motor disturbances such as clumsiness, muscle weakness, rigidity, inability to coordinate movement, and/or muscle spasms especially of the neck, spine, arms [thinkgenetic.com]
Drugs can be given to relieve muscle spasms, treat infections and try to control seizures (should they occur). Pain relief and sedative drugs can be given if required, and feeding can be assisted. [gosh.nhs.uk]
Some MLD Symptoms: Walking difficulties Hypotonia: low muscle tone Muscle spasms and cramps Strabismus : cross-eyed Spasticity: increased reflexes Nystagmus: involuntary eye movement Loss of sight Swallowing problems Decreased speech Seizures Ataxia: [leukodystrophyresourceresearch.org]
Symptoms start in the first few months of life and include: Muscle weakness Stiff limbs Trouble walking Vision and hearing loss Muscle spasms Seizures Metachromatic leukodystrophy ( MLD ): You can get MLD if you don’t have the enzyme arylsulfatase A. [webmd.com]
- Muscle Hypotonia
The first symptom is usually an unsteady gait due to muscle hypotonia. There are signs of a progressive polyneuropathy, ending in a generalized flaccid paresis of the arms and legs and a loss of tendon reflexes. The neuropathy may be painful. [78stepshealth.us]
Patients with the early juvenile form (4-6 y) tend to present with loss of motor developmental milestones; the most obvious signs are gait disturbances, ataxia, hyperreflexia followed by hyporeflexia, seizures, and decreased cognitive function. [emedicine.com]
[…] tetraplegia 33 HP:0002445 26 hallucinations 33 HP:0000738 27 spastic tetraplegia 33 HP:0002510 28 babinski sign 33 HP:0003487 29 dystonia 33 HP:0001332 30 abnormality of the musculature 60 Occasional (29-5%) 31 mental deterioration 33 HP:0001268 32 hyporeflexia [malacards.org]
Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. [ncbi.nlm.nih.gov]
[…] especially the cerebral hemispheres, due to defects in the formation and maintenance of myelin in infants and children Inherited, demyelinating, human lipid storage disease caused by a deficiency of galactosylceramidase; manifestations include convulsions, quadriplegia [icd9data.com]
Hypotonia: decreased muscle tone Esotropia: cross-eyed Psychomotor regression Clumsiness Spasticity: increased reflexes Nystagmus: type of abnormal eye movement Weakness Decreased speech Seizures Ataxia: loss of the ability to coordinate muscular movement Quadriplegia [ulf.org]
Workup of metachromatic leukodystrophy consists of a history and physical exam, nerve conduction testing, cerebrospinal fluid (CSF) evaluation, and imaging tests. A definitive diagnosis can be established with genetic testing.
The diagnosis of metachromatic leukodystrophy is established by demonstrating reduced arylsulfatase A gene activity in cultured skin fibroblasts or leukocytes. However, a diagnosis based only on the activity of ARSA should be differentiated from ARSA pseudodeficiency, which is present in about one percent of the population . Arylsulfatase A pseudodeficiency can be differentiated form metachromatic leukodystrophy by performing a radiolabeled sulfatide fibroblast loading test, assessment of sulfatide levels in the urine, and/or genetic analysis for mutations .
Prenatal testing can be performed by measurement of arylsulfatase A activity to identify carriers. Newborn screening is done using immune-quantification assays which screen numerous lysosomal proteins .
Magnetic resonance imaging (MRI) shows symmetric lesions in the white matter; lesions are predominant in the periventricular region during the early stages of the disease  . Late stage disease is characterized by cortical atrophy  . Results of clinical trials have shown that N-acetylaspartate levels, which are measured by magnetic resonance spectroscopy, may act as a marker of disease progression .
Nerve conduction studies demonstrate reduced nerve conduction velocity; in the early stages of the disease, sensory potentials are affected more severely than motor responses  . A peripheral nerve biopsy, which is often not necessary for diagnosis, is characterized by segmental demyelination with metachromatic material in schwann cells and macrophages. Neurocognitive and neuropsychological testing may be performed when clinically indicated.
For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. [ncbi.nlm.nih.gov]
Clinical evaluation: The patients will undergo clinical assessment prior to starting the treatment and at the end of the treatment period. [clinicaltrials.gov]
So proper counseling was done regarding the bad prognosis of the disease with symptomatic treatment. [ncbi.nlm.nih.gov]
PROGRESSION The prognosis for MLD is poor. In young children with MLD late infantile form, progressive loss of motor and cognitive functions is rapid. Death usually results within five years after the onset of clinical symptoms. [secure.ssa.gov]
Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment Diane F van Rappard 1, 2, Antoine Klauser 3, Marjan E Steenweg 1, 2, Jaap Jan Boelens 4, Marianna Bugiani 1, 2, 5, Marjo S van der Knaap 1, 2, Nicole [jnnp.bmj.com]
The leukodystrophies constitute a wide spectrum of cerebral disorders of varying etiology. [ncbi.nlm.nih.gov]
Based on epidemiological surveys the incidence of MLD per 100,000 live births varied from 0.6 to 2.5. [ncbi.nlm.nih.gov]
Based on epidemiological surveys the incidence of MLD per 100 000 live births varied from 0.6 to 2.5. [journals.plos.org]
Epidemiology Frequency United States Incidence is estimated to be 1 case per 40,000 births. Mortality/Morbidity Morbidity and mortality rates vary with each form of the disease. [emedicine.com]
Cerebral inflammation may contribute to the pathophysiology of MLD. To date, cytokine levels in the cerebral spinal fluid of MLD patients have not previously been reported. [ncbi.nlm.nih.gov]
For detailed information regarding the different forms of MLD, its genetics, pathophysiology, diagnosis, genetic counseling, treatment options, visit ELA page on MLD. [leukotreat.eu]
X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Biochim Biophys Acta. 2012 Sep;1822(9):1465-74. [maladiesrares-paris-sud.aphp.fr]
Pathophysiology In patients, the inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes metachromatic leukodystrophy. [emedicine.com]
Importantly, we finally show how a careful acid-base balance monitoring and prompt correction of imbalances might prevent severe consequences of acidosis. [ncbi.nlm.nih.gov]
HSC gene therapy can prevent progression of metachromatic leukodystrophy. Magnetic resonance (MR) images of the brain of a patient (MLD01) before and after gene therapy. The brain of this patient appeared largely normal 2 years after treatment. [doi.org]
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