**2.7.4 Globoid leukodystrophy (GLD)**

GLD or Krabbe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of galactocerebrosidase (GALC), an enzyme responsible for degrading betagalactocerebroside, a major component of myelin sheath. GALC deficiency causes defective and decreased myelination and inflammation in the CNS and peripheral nervous systems from catabolic derivatives of beta-galactocerebroside such as psychosine. These changes lead to progressive deterioration in neurologic and cognitive function, resulting in spasticity, mental deterioration, blindness, deafness, seizures and early death. In the most severe "early onset or infantile" form, children develop symptoms before 6 months of age and usually die by age 2. In the "late onset" form, symptoms appear in early to late childhood, but only a few children survive into teenage years.

HSCT is the only available therapy with potential to improve neurocognitive function, increase survival and alter the natural history of the disease. Krivit and colleagues (Krivit et al., 1998) described the use of allogeneic HSCT to treat 5 patients with GLD (4 received HLA-sibling HSCT & 1 unrelated cord). Two children with late onset GLD had substantial neurologic disability and they had resolution of their symptoms after transplant. Cognition, language and memory continued to develop normally in 3 children with late-onset disease. Most children had improvement in MRI, CSF protein levels, and all had normalization of enzyme activity. These findings support the use of allogeneic HSCT for children with GLD. If a matched related donor is not available, unrelated cord blood has also been shown to be beneficial (Escolar et al., 2005)**.** 

#### **2.7.5 Metachromatic leukodystrophy (MLD)**

MLD is an autosomal recessive lysosomal disorder arising from deficiency of arylsulfatase A (ARSA) enzyme activity and characterized by increased urinary sulfatides. The clinical phenotype is a broad continuous spectrum ranging from early-infantile MLD to adult-onset forms. Clinical symptoms vary depending on timing of presentation (infantile, juvenile or adult form), but all include abnormal cognitive skills, behavioral abnormalities with adults having mental regression and psychiatric symptoms, progressive spastic disease and increased CSF protein.

The first BMT for MLD was performed more than 20 years ago. According to the EBMT and CIBMTR registries, more than 100 transplants have since been performed for this disorder. Despite this number, the lack of graft-outcome and long-term follow up studies makes it difficult to draw firm conclusions regarding the efficacy of HSCT in MLD. In addition, data suggest that outcomes are less promising than those for MPS IH. It is not clear if MLD patients, or which phenotypes, might benefit from HSCT. For presymptomatic juvenile and adult onset patients there is positive evidence. Improved transplantation techniques and the prompt availability of CB grafts may positively influence long-term outcomes. An international registry would facilitate comparative evaluation of therapeutic options, leading to improved guidelines.
