Goucher Disease

Epidemiology:

• Common in Ashkenazi Jews- 1 in 850 live births
• General population- 1 in 50,000- 1,00,000
• Selective advantage is identified because of greater resistance to tuberculosis, superior intelligence and increased fertility.

Etiology:

• Occurs due to deficiency of beta glucocerebrosidase
• Gene located on chromosome 1q21
• Over 300 mutations have been identified
• Inherited in autosomal recessive pattern

Pathogenesis:

• Accumulation of sphingolipids within phagocytic cells throughout the body

Classification:

• Type 1- Chronic non neuronopathic- Prominent visceral symptoms
• Type 2- Acute neuronopathic symptoms. Seen at <2years of age
• Type 3- Chronic neuronopathic symptoms. Seen at >2years of age

Clinical Features:

• Splenomegaly
• Pancytopenia due to hypersplenism and bone marrow infiltration of Goucher cells
• Hepatomegaly
• Pathological fractures due to cortical erosions, osteopenia, and avascular infarction
• Delayed eruption of teeth
• Delayed menarche and menorrhagia
• Neurological problems- Seen in Type II and III- Dementia, myoclonic seizures, mental retardation, oculomotor abnormalities, opisthotonos, peripheral neuropathy

Investigations:

• Bone marrow aspiration- Goucher cells- Large macrophages with eccentric nucleus and abundant wrinkled cytoplasm. Inclusions are PAS positive.
• Peripheral smear- Leucoerythroblastic blood picture
• Serum beta glucuronidase- Decreased
• Glucocerebrosidase activity in WBCs- Decreased
• Detection of specific mutations
• X-Ray- Expansion of distal femoral cortex (Erlenmeyer Flask deformity)

Treatment:

• Splenectomy to relieve symptoms of massive splenomegaly
• Rec. Glucocerebrosidase (imiglucerasecerezyme)
  • 15-60Units/Kg- IV- Biweekly
  • Neurological symptoms do not subside as enzyme cannot cross blood brain barrier
• Oral Miglustat- Inhibitor of glucocerebrosidesynthase- 100mg- TDS
• Velaglucerase alfa- 60units/ Kg- IV- Once in 2 weeks
• Orthopedic procedures for pathological fractures
• Transfusion support for cytopenia
• Allogeneic stem cell transplantation- Can be a cure, as macrophages are descendants of hematopoietic stem cells.

Nieman Pick disease

Epidemiology:

• Common in Ashkenazi Jews

Etiology:

• Deficiency of sphingomyelinase causing accumulation of sphingomyelin/ cholesterol
• Autosomal recessive inheritance

Classification:

• Type A- Severe infantile form with extensive neurological involvement. Progressive wasting, blindness, deafness and early death (within 3 years of life)
• Type B- No neurological involvement and patient survives into adulthood. Presents with hepatosplenomegaly.
• Type C- Neuropathic with onset of disease in early childhood. Can have neonatal jaundice. Neurological manifestations include dementia, ataxia, dysarthria, dystonia and seizures.

Clinical Features:

• Hepatosplenomegaly
• Anemia with bleeding
• Retinal cherry spot

Investigations:

• Hemogram- Mild anemia and thrombocytopenia, >75% of lymphocytes contain 1-9 vacuoles with diameter of 2 microns.
• Bone marrow- Macrophages with foamy cytoplasm.
• Sphingomyelinase level in leucocytes or cultured fibroblasts- Decreased

Treatment:

• Splenectomy- Rarely required
• Substrate reduction therapy- Miglustat- 200mg- TDS. Approved for type III disease.
• No much use of cholesterol low diet, liver transplantation or bone marrow transplantation

Related Disorders:

• Wolman disease
  • Deficiency of lysosomal acid lipase that hydrolyse cholesterol esters
  • Lethal in 6 months of age
  • Clinical features- Failure to thrive, hepatosplenomegaly, adrenal calcification and necrosis
• Farber disease
  • Deficiency of ceramidase
  • Accumulation of ceramide and other gangliosides in the skin, lymph nodes, brain and viscera
• Krabbe disease (Globoid leukodystrophy)
  • Deficiency of beta galactosidase
  • Accumulation of galactosylceremide in nervous system
  • Globoid cells- Microglial macrophages which are large multinucleated cells with PAS positive material.
• Fabry’s disease
  • X linked disorder
  • Deficiency of alpha galactosidase A
  • Accumulation of glycosphingolipids in tissues throughout the body- eyes, heart, skeletal muscle, nervous system, endothelium, smooth muscles and kidneys.
  • Presents with painful paresthesia of hands and feet.
• TaySach disease
  • Deficiency of hexosaminidase alpha subunit
  • Accumulation of GM2 gangliosides
  • Neurons are ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides.
  • Progressive destruction of neurons with proliferation of microglia.
  • Presents at 6 months of age with motor and mental deterioration, muscular flaccidity, blindness and increasing dementia. Over 1-2 years patients reach a complete vegetative stage.
• Mucopolysaccharidosis
  • Deficiency of enzymes that hydrolysemucopolysaccharides such as heparin sulfate and chondroitinsulphate.
  • All are autosomal recessive except Hunter syndrome which is X linked recessive.
  • Clinical features
    • Coarse facial features
    • Clouding of cornea
    • Joint stiffness
    • Mental retardation
    • Hepatosplenomegaly
    • Valvular lesions