Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (438 page)

BATTEN DISEASE (CLN3, BATTEN-SPIELMEYER-VOGT DISEASE, NEURONAL CEROID LIPOFUSCINOSIS)

MIM #204200

   Definition

The neuronal ceroid lipofuscinoses (NCLs or CLNs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally.

   Who Should Be Suspected?

The clinical course includes progressive dementia, seizures, and progressive visual failure. CLN3 is especially prevalent in Finland with an incidence of 1:21,000 live births and a carrier frequency of 1 in 70.

   Relevant Tests and Diagnostic Value

   Enzyme testing for CLN1 or CLN2 is useful before ordering DNA mutation screening for affected individuals. Enzyme testing is not a reliable carrier test.

   Sequence analysis for mutations.

   Detection of a 1.02-kb deletion in the CLN3 gene at 16p11.2 present in the majority of Batten disease cases.

   The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a “fingerprint” profile, which can have three different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3.

   Other Considerations

Presentations of CLN are caused by mutations in eight genes. The CLNs were originally classified broadly by age at onset: CLN1 as the infantile-onset form or the infantile-onset Finnish form, having first been described in that population; CLN2 as the late infantile-onset form; CLN3 as the juvenile-onset and most common form; and CLN4 as the adult-onset form. With the identification of molecular defects, the CLNs are now classified numerically according to the underlying gene defect. For example, CLN1 refers to CLN caused by mutations in the
PPT1
gene, regardless of the age at onset.

Suggested Readings

International Batten Disease Consortium. Isolation of a novel gene underlying Batten disease, CLN3.
Cell.
1995;82:949–957.

Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses.
Neurogenetics.
2005;6: 107–126.

   
NEUROLOGIC DISORDERS

ALZHEIMER DISEASE (PRESENILE AND SENILE DEMENTIA)

MIM #104300

   Definition

Alzheimer disease (AD) is a progressive adult-onset dementia that typically begins with subtle memory failure that becomes more severe and incapacitating. Pathologic findings include cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. A genetic mutation in amyloid precursor protein (APP) that significantly decreases the amount of beta-amyloid by about 40% confers protection from developing Alzheimer’s.

   Who Should Be Suspected?