Metabolic Storage Disorders

Introduction

  • This entry will focus on the following metabolic atorage disorders:
    • Krabbe Disease
    • Metachromic Leukodystrophy
    • Fabry Disease

 

Krabbe Disease

  1. Also known as Globoid Cell Leukodystrophy
  2. Autosomal Recessive Inheritance
  3. Deficient enzyme: Galactocerebrosidase (galactosylceramidase)
    1. Responsible for liposomal hydrolysis of galactolipids that are formed during white matter myelination
  4. Accumulated substrate: Galactocerebroside & Psychosine
  5. Pathology: shows PAS positive multinucleated globoid cells in the CNS (blue arrows)

krabbe.pnghttp://missinglink.ucsf.edu/lm/ids_104_Demyelination/Didactic/Leukodystr...

  1. Clinical features: 3 Distinct patterns of onset
    1. Infantile Onset (most common): Symptoms manifest in 2 – 5 months. Symptoms include developmental delay, limb spasticity, axial hypotonia, optic atrophy, absent reflexes, eventual seizures. Death occurs within 2 years.
    2.  Juvenile Onset: Weakness, vision loss, loss of skills. Death occurs within 2 – 7 years.
    3. Adult Onset: Loss of manual dexterity, burning paresthesias, weakness, peripheral motor sensory neuropathy, muscle atrophy with scoliosis. Variable effect on intellectual deterioration.
  2. Diagnosis: Galactocerebrosidase enzyme activity < 5% of the normal value in leukocytes from blood or cultured skin fibroblasts
  3. Management/ Treatment
    1. Only supportive care available for infantile onset
    2. Preliminary studies with hematopoietic stem cell transplantation has provided some therapeutic benefit
      1. However, initial studies have only proven HSC transplantation beneficial if administered in the pre-symptomatic stage of the disease
  4. Additonal Info:
    1. http://www.huntershope.org
      1. Website/ foundation for family information about Krabbe disease founded by former NFL player Jim Kelly whose son had Krabbe disease

 

Metachromatic Leukodystrophy (sulfatide lipidosis)

  1. Autosomal recessive inheritance
  2. Prevalence: 1:40,000 to 1:100,00
    1. Increased prevalence in Habbanite Jews, Israeli Arabs, and Navajo Indians
  3. Deficient Enzyme: Arylsulfatase A; typically mutations in the arylsulfatase A (ARSA) gene
    1. Enzyme is responsible for the desulfonation of the major myelin glycolipid, cerebroside sulfate
  4. Accumulated substrate: Cerebroside sulfate accumulates in CNS, PNS, kidneys, and other visceral organs
    1. Accumulation of cerebroside sulfate results in destruction of oligodendrial and Schwann cells, resulting in demyelination
  5. Pathology:  sulfatide containing macrophages in the CNS (red arrow)
    1. Metachromasia an effect seen when the sulfatides within macrophages bind different staining dyes

metachromicLD.pnghttp://missinglink.ucsf.edu/lm/ids_104_Demyelination/Didactic/Leukodystr...

  1. Clinical features: Three major subtypes distinguished by age of onset
    1. Late Infantile: Regression of motor skills, gait difficulties, ataxia, seizues, hypotonia, optic atrophy. Worse prognosis than later onset forms, death within 5 – 6 years.
    2. Juvenille: Further subdivided into early juvenile (present at 4 – 6 years old) and late juvenile (6 – 16 years old). Both types present with intellectual impairment and seizures. Early juvenile is more severe, additionally presenting with ataxia, upper motor neuron signs, and peripheral neuropathy, with occurring within 6 years of onset.
    3. Adult: Age 17 or older; dementia, behavioral difficulties, and optic atrophy are common.  Specific subsets present with neuropathy, psychosis, seizures, and schizophrenia.
  2. Diagnosis:
    1. Suspected based on clinical picture (see above) with reduced nerve conduction velocity and elevated protein in CSF
    2. Confirmatory test demonstrates arylsulfatase A activity that is <10% of normal values in leukocytes or cultured skin fibroblasts
  3. Management/ Treatment:
    1. No curative treatment is currently available
    2. Preliminary evidence suggests that gene therapy, HSC transplantation combined with gene therapy, and enzyme replacement therapy show promise
      1. Lentiviral vectors used to transfer functional ARSA genes into autologous HSCs and then transfused back into their respective patients, has resulted in each patient showing no evidence of disease progression at 21 months of follow up
  4. Additional Info:
    1. http://www.mldfoundation.org/index.php
      1. Website with information and research for families affected by metachromatic leukodystrophy
    2. http://www.mldfoundation.org/mld-video-player.php?video=108

 

Fabry Disease (lipidosis)

  1. Second most prevalent lysosomal storage disease
    1. 1:17,000 – 1:117,000 males, likely higher due to frequently missed or late diagnosis
  2. X-linked recessive inheritance
  3. Deficient Enzyme:  alpha-galactosidase A
    1. Lysosomal hydroxylase enzyme that catalyzes cleavage of terminal galactose from globotriaosylceramide, leading to its accumulation in the spleen, kidney, liver, and bone marrow
  4. Accumulated substrate: globotriaosylceramide (ceramide trihexoside)
  5. Pathology: glycolipid inclusion bodies in distal renal tubules, although tissue biopsy is rare (stained blue in image below)
  6. Clinical features: presentation often occurs in a predictable order in classically affected males

tableMSD_0.png

  1. Diagnosis: less than 10% alpha-Galactosidase A activity in leukocytes or cultured skin fibroblasts
  2. Treatment:
    1. No curative treatment exists
    2. Treatment focused on replacing missing or deficient enzyme, alpha-galactosidase A
    3. Additional care involves multi-disciplinary management of complications including neurology, nephrology, and cardiology
      1. ACE inhibitors or ARB are a mainstay of reno-protective treatment
      2. Carbmazapine or other anti-convulsants thought to help with pain, but NSAIDS should be avoided as the increase likelihood of renal toxicity
  3. Additional Info:
    1. http://www.fabrydisease.org/

References:

  1. "Leukodystrophies." Leukodystrophies. USCF Neurobiology Department. Web. 10 Aug. 2015.
  2. Siddiqi ZA, Sanders DB, Massey JM. Peripheral neuropathy in Krabbe disease: effect of hematopoietic stem cell transplantation. Neurology 2006; 67:268.
  3. Staretz-Chacham, Orna, et al.  Lysosomal Storage Disorders in the Newborn.  Pediatrics, 123:1191-1207.  2009.
  4. Desnick, RJ, et al. Enzyme Replacement Therapy for Lysosomal Storage Diseases: Lessons from 20 years of Experience and Remaining Challenges. Annual Review of Genomics and Human Genetics, 13:307-335. 2012.
  5. Kohlschütter A. Lysosomal leukodystrophies: Krabbe disease and metachromatic leukodystrophy. Handb Clin Neurol. 2013;113:1611–8.
  6. Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy--an update. Neuropediatrics. 2010 Feb;41(1):1–6.
  7. Hollak CEM, Weinreb NJ. The attenuated/late onset lysosomal storage disorders: Therapeutic goals and indications for enzyme replacement treatment in Gaucher and Fabry disease. Best Pract Res Clin Endocrinol Metab. 2015 Mar;29(2):205–18.
  8. Arends M, Hollak CEM, Biegstraaten M. Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet J Rare Dis. 2015;10:77.

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