Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD. La leucodistrofia metacromática es una enfermedad progresiva hereditaria y neurodegenerativa. Un paciente que sufre de esta enfermedad representa. Request PDF on ResearchGate | Leucodistrofia metacromática. Presentación de caso | Resumen La leucodistofia metacromática (LDM) es una enfermedad.
|Published (Last):||14 May 2015|
|PDF File Size:||11.55 Mb|
|ePub File Size:||15.66 Mb|
|Price:||Free* [*Free Regsitration Required]|
University of Washington, Seattle; May 30, ; Last Update: Arylsulfatase A deficiency also known as metachromatic leukodystrophy or MLD is characterized by three clinical subtypes: Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms.
Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and metacromtaica. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, leucodistrofiia have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Onset is between age 30 months and 16 years.
Initial manifestations include ,eucodistrofia in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade.
Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms weakness and loss of coordination progressing to spasticity and incontinence metacromstica seizures initially predominate. Peripheral neuropathy is common. Disease course is variable — with periods of stability interspersed with periods of decline — and may extend over two to three decades.
The final stage is similar to earlier-onset forms. The diagnosis of MLD is established in a proband with progressive neurologic dysfunction, MRI evidence of leukodystrophy, or ARSA enzyme deficiency and identification of biallelic ARSA pathogenic variants on molecular genetic testingor identification of elevated urinary excretion of sulfatides, or less commonly, identification of metachromatic lipid deposits in nervous system tissue.
Standard treatments for gastroesophageal reflux, constipation, drooling, dental care, pulmonary function, and impaired vison. Prevention of primary manifestations: Hematopoietic stem cell transplantation HSCT is the only therapy for primary central nervous system manifestations.
Outcomes depend on the clinical stage and the presence of neurologic symptoms. The best results are observed when HSCT is performed in pre- and very early symptomatic individuals with the juvenile or adult form of the disease.
Prevention of secondary complications: Therapies designed to prevent decline in mobility, cognitive ability, communication, or food intake; safety metcromatica for movement limitations and seizure precautions.
Regular monitoring by a neurologist or metabolic geneticist including evaluation for changes in motor function, development of seizures, contractions, feeding difficulties, and disease progression following anesthesia or fever; periodic brain MRI examination. MLD is inherited in an autosomal recessive manner.
Carrier testing of at-risk family members and prenatal testing for leucodistrovia pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member. Arylsulfatase A deficiency also known as metachromatic leukodystrophy or MLD should be suspected in individuals with the following:.
Pseudodeficiency is difficult to distinguish from true ARSA enzyme deficiency by biochemical testing alone. The term has been applied to other enzyme deficiency disorders, such as hexosaminidase A deficiencywhere specific variants are associated with reduced enzymatic activity when measured using synthetic substrate but have normal enzymatic activity when measured using a natural substrate. Newborn screening for MLD based on enzyme activity has been difficult due to the high occurrence of ARSA enzyme pseudodeficiency and the inability to distinguish MLD from metacromatida.
A mass spectrometry-based method to quantify sulfatides in dried blood and urine spots has been developed [ Spacil et al ] and a large-scale pilot study for newborn screening to evaluate this method for sulfatide analysis in dried blood spots has begun at the University of Washington, Seattle.
The diagnosis of arylsulfatase A deficiency metachromatic leukodystrophy, MLD is established in a proband by the presence of suggestive findings metqcromatica. Molecular genetic testing approaches can include single- gene testinguse of a multigene paneland more comprehensive genomic testing.
Parental testing may be necessary to determine the phase of the identified variants in the proband:. View in own window. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this metarcomatica. Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic.
For issues to consider in interpretation of sequence analysis results, click here. Four pathogenic variants c.
ProLeuleucodistofia p. Using scanning for pathogenic variants, Gort et al  identified all of the ARSA pathogenic variants in 18 unrelated affected persons of Spanish heritage. Methods that may be used include: No instances of whole- gene duplication are known.
Arylsulfatase A Deficiency – GeneReviews® – NCBI Bookshelf
Dispermic chimeris, in which two copies of ARSA were transmitted by the father, has been reported [ Coulter-Mackie et al ]. All types of MLD excrete leeucodistrofia high sulfatides in urine.
TLC is a semi-quantitative method. For HPCL and mass spectrometry, reference and pathologic values vary by laboratory. Because urine production is highly variable, sulfatide excretion is measured in a hour urine sample or leucodistrofix to the urinary excretion of creatinine. Elevated urine sulfatides and ARSA enzyme deficiency in the presence of metacrokatica features, dysostosis multiplex, mdtacromatica ichthyosis should prompt evaluation for multiple sulfatase deficiency see Differential Diagnosis.
Sulfatides interact strongly with leycodistrofia positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia.
When frozen tissue sections are treated with acidified cresyl violet Hirsch-Peiffer stainsulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in leucpdistrofia system tissue is pathognomonic for MLD. The clinical presentation of arylsulfatase A deficiency metachromatic leukodystrophy, MLD is heterogeneous with respect to the age of onset, the rate of leucodiztrofia, and the initial symptoms.
Three clinical subtypes of MLD are primarily distinguished by age of onset:. The age of onset within a family is usually similar, but exceptions occur [ Arbour et al ].
Although the presenting symptoms and age of onset vary, all individuals eventually develop complete loss of motor, sensory, and intellectual functions. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms [ Von Figura et al ].
Death most commonly results from pneumonia or other infection. Life span correlates roughly with the age of onset but can be quite variable, particularly in the later-onset forms. Age of onset is before age 30 months, following a period of apparently normal development.
In the initial stage, weakness, hypotonia, and depressed deep tendon reflexes are observed. Clumsiness, frequent falls, toe walking, and dysarthria are other typical presenting signs. Symptoms may first be noted following anesthesia or a febrile illness and may subside for weeks leucodistrovia continuing to progress. Less commonly, seizures are the first neurologic sign. Seventy-five percent of individuals show first motor symptoms before age 18 months [ Kehrer et al a ].
Peripheral neuropathy with slow nerve conduction velocities NCVs is common.
Brain auditory and visual evoked response testing demonstrate impairment in hearing and vision. As the disease progresses, language, cognitive development, and gross- and fine-motor skills regress.
Peripheral neuropathy can lead to pain in the arms and legs. In one study, individuals with the late-infantile form had lost the ability to sit without support and to move by age three years, and all had lost both trunk and head control by age three years four months [ Kehrer et al a ]. Eventually spasticity becomes prominent and bulbar involvement can result in airway obstruction and feeding difficulties requiring gastrostomy tube placement.
Generalized or partial seizures can occur and vision and hearing become progressively compromised. Eventually, the child becomes bedridden with tonic spasms, decerebrate posturing, and general unawareness.
Most children die within five years after the onset of symptoms, although survival can extend into the second decade of life with current levels of care. Age of onset is between ages 30 months and 16 years with a median age of six years two months [ Kehrer et al a ]. Symptoms start insidiously with a decline in school performance, abnormal behaviors, or psychiatric symptoms. Early- and late-juvenile subvariants are sometimes differentiated, neuromuscular difficulties developing first in individuals with earlier-onset MLD and behavioral issues developing first in individuals with later-onset MLD.
The rate of motor deterioration can be quite variable [ Kehrer et al a ]. The majority of individuals die before age 20 years, but survival is quite variable.
As with juvenile MLD, presenting symptoms vary. Initial signs are often emerging problems in school or job performance. Alcohol or drug use, poor money management, emotional lability, inappropriate affect, and frank psychosis often lead to psychiatric evaluation and an initial diagnosis of dementia, schizophrenia, or depression.
In others, neurologic symptoms weakness and loss of coordination progressing to spasticity and incontinence predominate initially, leading to diagnosis of multiple sclerosis or other neurodegenerative diseases. Peripheral neuropathy, though a frequent aspect of adult-onset MLD, is not present in all individuals. The course is variable.
Periods of relative stability may be interspersed with periods of decline. Inappropriate behaviors and poor decision making become problems for the family or other caregivers.
Dressing and other self-help skills deteriorate. Eventually, bowel and bladder control is lost. As the disease advances, dystonic movements, spastic quadriparesis, or decorticate posturing occurs. Severe contractures and generalized seizures may occur. The duration of the disease ranges from several years to decades. Arylsulfatase A deficiency is a disorder of impaired breakdown of sulfatides cerebroside sulfate or sulfo-galactosylceramidesulfate-containing lipids that occur throughout the body and are found in greatest abundance in nervous tissue, kidneys, and testes.
Sulfatide accumulation in the nervous system eventually leads to myelin breakdown leukodystrophy and a progressive neurologic disorder [ Von Figura et al ].
There are substantial limitations to the use of these genotype-phenotype correlations in predicting the clinical presentation and natural history of an affected individual.