Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.

BACKGROUND: In GM1 gangliosidosis the lack of function of ß-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce. METHODS: We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases. CONCLUSION: This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.

The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression.

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

Biotinidase deficiency due to a de novo mutation or gonadal mosaicism in a first child.

Biotinidase deficiency (BD), which is caused by BTD genetic lesions, if untreated, can result in neurological and cutaneous manifestations. Biotin supplementation can improve or prevent symptoms. We herewith present a family, which we studied at biochemical and molecular level, after identifying the proband through a newborn screening programme. BTD gene molecular analysis showed the proband to be compound heterozygous for the c.1330G>C p.(Asp444His) mild known variant, and for the c.1475 C>T p.(Thr492Ile) new variant. Bioinformatic analysis allowed us to confirm the pathogenic role of the newly identified variant. The proband's father, who exhibited low biotinidase (BTD) enzyme activity, was homozygous for the mild variant, whereas the proband's mother, who exhibited borderline BTD values, the BTD mutation carrier status could not be detected. This is the first description of a patient with BD harbouring a variant whose origin is either de novo or the consequence of gonadal mosaicism. BTD molecular analysis and bioinformatic tools for the evaluation of pathogenicity of newly identified variants are necessary for diagnostic purposes (i.e., clarifying borderline enzyme assays and the carrier status of parents), and for genetic counselling.