Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines.

PURPOSE: To describe a diagnostic protocol, surveillance and treatment guidelines, genetic counseling considerations and long-term follow-up data elements developed in preparation for X-linked adrenoleukodystrophy (X-ALD) newborn screening in New York State. METHODS: A group including the director from each regional NYS inherited metabolic disorder center, personnel from the NYS Newborn Screening Program, and others prepared a follow-up plan for X-ALD NBS. Over the months preceding the start of screening, a series of conference calls took place to develop and refine a complete newborn screening system from initial positive screen results to long-term follow-up. RESULTS: A diagnostic protocol was developed to determine for each newborn with a positive screen whether the final diagnosis is X-ALD, carrier of X-ALD, Zellweger spectrum disorder, acyl CoA oxidase deficiency or D-bifunctional protein deficiency. For asymptomatic males with X-ALD, surveillance protocols were developed for use at the time of diagnosis, during childhood and during adulthood. Considerations for timing of treatment of adrenal and cerebral disease were developed. CONCLUSION: Because New York was the first newborn screening laboratory to include X-ALD on its panel, and symptoms may not develop for years, long-term follow-up is needed to evaluate the presented guidelines.

Krabbe disease: clinical, biochemical and molecular information on six new patients and successful retrospective diagnosis using stored newborn screening cards.

PURPOSE: To present clinical, biochemical and molecular information on six new clinically diagnosed Krabbe disease patients and assess the sensitivity of retrospective galactocerebrosidase measurement in their newborn screening samples. METHODS: Medical records were reviewed. Galactocerebrosidase activity was measured in leukocytes and, retrospectively, in the patients' newborn screening cards (stored for 1.4 to 13.5 years). GALC gene mutation analysis was performed. RESULTS: Five patients with Krabbe disease, one of whom also had hydrocephalus, became symptomatic during infancy. A sixth patient presented with seizures and developmental regression at age two and had a protracted disease course. Galactocerebrosidase activity in leukocytes ranged from 0.00 to 0.20 nmol/h/mg protein. Low galactocerebrosidase activity (range: 3.2% to 11.1% of the daily mean), consistent with Krabbe disease, was detected in each of the newborn screening samples. GALC molecular analysis identified six previously unreported mutations and two novel sequence variants. CONCLUSION: Our cases highlight the clinical variability of Krabbe disease. Galactocerebrosidase activity in newborn dried blood spots is a highly sensitive test, even when samples have been stored for many years. The high frequency of private mutations in the GALC gene may limit the use of genetic information for making treatment decisions in the newborn period.

Linkage of hereditary distal myopathy with desmin accumulation to 2q.

We are investigating the genetics of a large family with an autosomal dominant form of hereditary distal myopathy. This slowly progressive myopathy begins during early adulthood in the distal leg muscles, producing a gait disturbance. Cardiomyopathy is also present in most affected family members, manifesting itself as conduction block or congestive heart failure. Histologically, an accumulation of the protein, desmin, occurs in the subsarcolemmal spaces of myofibers. We have performed linkage analyses of this family, and have mapped the location of the gene causing the myopathy to human chromosome 2q33. The gene is within a 17-cM segment of chromosome 2q bounded by the DNA markers D2S2248 and D2S401. The best candidate gene for this myopathy is desmin.

A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filament formation.

In some myopathies of distal onset, the intermediate filament desmin is abnormally accumulated in skeletal and cardiac muscle. We report the first point mutation in desmin cosegregating with an autosomal dominant form of desmin-related myopathy. The L345P desmin missense mutation occurs in a large, six generation Ashkenazi Jewish family. The mutation is located in an evolutionarily highly conserved position of the desmin coiled-coil rod domain important for dimer formation. L345P desmin is incapable of forming filamentous networks in transfected HeLa and SW13 cells. We conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.