New! 147

## Abstract

Abstract

1. Infantile globoid cell leukodystrophy (GLD, also called Krabbe disease; OMIM #245200) is a rapidly progressive, invariably fatal disease. It is transmitted as an autosomal recessive trait. The disease usually begins between 3 and 6 months of age with nonspecific symptoms such as stiffness, feeding difficulties, and irritability, but soon progresses to motor deterioration and cognitive decline. Clinical manifestations are limited to the nervous system, with prominent corticospinal tract signs. Patients experience hypertonia with decreased deep tendon reflexes in the early stages, but later become flaccid and hypotonic. Visual deficits are common. Peripheral neuropathy is almost always detectable. Patients rarely survive the second year. While the infantile form is the most common, later onset forms are also recognized. While there is no clear delineation of subtypes, clinical manifestations can begin at any age after infancy. Patients with later onset forms usually present with ataxia, weakness, blindness, spastic paraparesis, behavioral problems, and dementia.

2. The presence of numerous, often multinucleated, globoid cells, the almost total loss of myelin and oligodendroglia, and astrocytic gliosis in the white matter are the morphologic basis for diagnosis. The globoid cells are hematogenous macrophages that contain undigested galactosylceramide. Segmental demyelination, axonal degeneration, fibrosis, and histiocytic infiltration are common in the peripheral nervous system. It is postulated that accumulation of a toxic metabolite, psychosine (galactosylsphingosine), which is also a substrate for the missing enzyme, leads to the death of myelin-forming cells. However, the extensive globoid cell reaction indicates that impaired catabolism of galactosylceramide is also an important factor in the pathogenesis.

3. Consistent with the myelin loss, the white matter is severely depleted of all lipids, particularly glycolipids. However, the ratio of galactosylceramide to sulfatide is abnormally high. Galactosylceramide, a sphingoglycolipid consisting of sphingosine, a fatty acid, and galactose, is an important component of the myelin sheath.

4. The primary cause of Krabbe disease is a genetic deficiency of galactocerebrosidase (GALC; EC 3.2.1.46) activity. This lysosomal enzyme normally degrades galactosylceramide to ceramide and galactose. A few infants with a clinical picture similar to Krabbe disease have been found to have mutations in saposin A, an activator protein that assists in the action of GALC on galactosylceramide.

5. Assays of GALC activity in leukocytes or cultured fibroblasts using an appropriate substrate can readily establish a definitive diagnosis. Intrauterine diagnosis of affected fetuses in at-risk couples is available using amniotic fluid cells or biopsied chorionic villi by mutation analysis when the parents’ genotypes have been identified. Knowing the mutation(s) also opens the possibility of preimplantation genetic diagnosis.

6. In an attempt to arrive at an early diagnosis, newborn screening for Krabbe disease has been initiated in New York State. The method involves an enzyme-based assay using dried blood spots and tandem mass spectrometry followed by conventional testing and sequencing in the event of a low GALC value.

7. Treatment at this time is limited to hematopoietic stem cell transplantation, often using umbilical cord blood stem cells, in asymptomatic individuals and those with only minimal neurologic involvement. This seems to slow the expected course of the disease with improved neurological function and magnetic resonance imaging findings and decreased cerebrospinal fluid protein.

8. The human GALC gene (OMIM *606890) has been mapped to chromosome 14q31. The human cDNA and gene have been cloned. The cDNA encodes a protein of 643 amino acids following cleavage of the leader sequence. The gene is about 56 kb, consisting of 17 exons. Over 140 disease-causing mutations have been found in patients with all types of GLD. However, a few specific mutations are found in a significant number of unrelated patients with European ancestry and within some inbred communities. In addition, a number of polymorphisms in this gene have been identified. Some of these polymorphisms can result in significantly lowered GALC activity resulting in wide “normal” and “carrier” ranges. These polymorphisms may also play a role in modifying the effect of other disease-causing mutations on the same allele.

9. GALC deficiency also occurs in other mammalian species, most notably in certain breeds of dogs, monkeys, and mice. Clinical and pathologic features are similar to those in the human disease. These animal models are currently being used in therapy trials.

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.