Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (425 page)

MIM, Online Mendelian Inheritance in Man, John Hopkins University: Farber Lipogranulomatosis,
http://www.ncbi.nlm.nih.gov/mim

GAUCHER DISEASE (ACID BETA-GLUCOSIDASE DEFICIENCY; GBA DEFICIENCY)

MIM #230800

   Definition

Gaucher disease, the most common lysosomal storage disorder, is caused by the autosomal recessively inherited deficiency of acid β-glucosidase (glucocerebrosidase; GBA). Mutations in the GBA gene, located at 1q21, result in accumulation of the glycosphingolipid glucosylceramide within lysosomes, predominantly in macrophages.

   Who Should Be Suspected?

Among individuals of Ashkenazi Jewish descent, the incidence of type 1 Gaucher disease is approximately 1 in 500–1,000, with a carrier frequency of approximately 1 in 15 individuals. In contrast, Gaucher disease is seen in only 1 in 50,000– 100,000 individuals in the general population.

   Classification

Type 1 (nonneuronopathic)
is the most common form of the disease and does not involve the CNS. The clinical manifestations of type 1 Gaucher disease are heterogeneous, can come to attention from infancy to adulthood, and can range from very mildly affected individuals to those having rapidly progressive systemic abnormalities.

Type 2
is very rare, rapidly progressive, and affects the brain as well as the organs affected in type 1 Gaucher disease. It is usually fatal by 2 years of age.

Type 3
. The signs and symptoms appear in early childhood, with onset much later than type 2. Some patients have ophthalmoplegia as the only neurologic abnormality, but more severe presentations are variable and include supranuclear horizontal ophthalmoplegia, progressive myoclonic epilepsy, cerebellar ataxia, spasticity and dementia, as well as the signs and symptoms seen in type 1.

   Relevant Tests and Diagnostic Value

Biochemical testing
—enzyme assay: Acid β-glucosylceramidase activity in WBCs (lymphocytes) or skin cells (fibroblasts). The overlap in the range of GBA enzyme activity values between noncarriers and Gaucher disease carriers makes enzyme testing only about 90% accurate for identification of carriers.

Molecular testing:

   Targeted mutation analysis: Available for four common mutations (N370S, L444P, 84GG, and IVS2 + 1G>A), which account for approximately 90% of the disease-causing alleles in the Ashkenazi Jewish population and 50–60% in non-Jewish populations. Some laboratories offer testing for additional seven “rare” mutations (V394L, D409H, D409V, R463C, R463H, R496H, and a 55-base-pair deletion in exon 9). DNA testing needs to distinguish mutations in the functional GBA gene from sequences present in the highly homologous GBA pseudogene.

   Sequence analysis: Analysis of the entire coding region or exons. More than 150 GBA gene mutations have been described. Non-Jewish individuals with Gaucher disease tend to be compound heterozygotes that include one common mutation.

Suggested Readings

Beutler E, Nguyen NJ, Henneberger MW, et al. Gaucher disease: gene frequencies in the Ashkenazi Jewish population.
Am J Hum Genet.
1993;52(1):85–88.

Horowitz M, Pasmanik-Chor M, Borochowitz Z, et al. Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population.
Hum Mutat.
1998;12(4):240–244. [Erratum in:
Hum Mutat.
1999;13(3):255.]

Tsuji S, Choudary PV, Martin BM, et al. A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher disease.
N Engl J Med.
1987;361:570–575.

GLYCOGEN STORAGE DISEASE, TYPE I (GLUCOSE-6-PHOSPHATASE DEFICIENCY, VON GIERKE DISEASE)

MIM #232200

   Definition

Glycogen storage disease (GSD) type I is the most common of the glycogen storage disorders. This genetic disease results from deficiency of either the enzyme glucose-6-phosphatase (type Ia) or a glucose-6-phosphate translocase transporter (type Ib). The lack of either glucose-6-phosphatase catalytic activity or glucose-6-phosphate translocase activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis, resulting in hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hepatomegaly, and renomegaly.

   Relevant Tests and Diagnostic Value

Chemistry:

   Fasting blood glucose concentration <60 mg/dL (reference range: 70–120 mg/ dL)

   Blood lactate >2.5 mmol/L (reference range: 0.5–2.2 mmol/L)