Initiation and discontinuation of substrate inhibitor treatment in patients with Niemann-Pick type C disease.

Niemann-Pick type C disease (NP-C) is a lysosomal storage disorder characterized by a progressive neurological deterioration. Different clinical forms have been defined based on patient age at neurological symptoms onset: perinatal, early infantile (EI), late infantile (LI), juvenile and adult. There is no curative treatment for NP-C. Miglustat is the first effective therapy for the neurological manifestations of NP-C patients, as it can slow down the progression of the disease. Our aim is to establish recommendations on the initiation and discontinuations with miglustat therapy based on the modified disability scale scores and describe therapeutic options to prevent treatment-related adverse effects. Four patients with different clinical forms of NP-C are reported. The modified disability scale was applied at baseline and treatment on follow up. Treatment with miglustat was initiated in patient 1 (EI form) at onset of delayed speech. Patient 2 (LI form) who started miglustat therapy in the advanced stage of the disease, died 2 years thereafter. Patient 3 (juvenile form) started treatment with miglustat at diagnosis and remains stable at four years on follow up. Patient 4, asymptomatic, is not currently treated. Miglustat has demonstrated efficacy to slow down the neurological impairment in NP-C patients assessed by the modified disability scale. Miglustat should be initiated at the onset of the first neurological symptoms. Disability scores above 20 reflect an advanced neurological impairment of the disease and miglustat therapy should be discontinued or not initiated. The gastrointestinal adverse effects can be prevented by dose titration and dietary modifications.

Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects.

BACKGROUND: Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency. OBJECTIVE: To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated. DESIGN: We studied the spectrum and frequency of disorders associated with cerebral folate deficiency by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins. Direct sequencing of the FOLR1 transporter gene was also performed in some patients. SETTING: Academic pediatric medical center. PARTICIPANTS: We studied 134 individuals free of neurometabolic disease and 584 patients with any of several diseases of the central nervous system. RESULTS: Of 584 patients, 71 (12%) exhibited 5-MTHF deficiency. Mild to moderate deficiency (n = 63; range, 19-63 nmol/L) was associated with perinatal asphyxia, central nervous system infection, or diseases of probable genetic origin (inborn errors of metabolism, white matter disorders, Rett syndrome, or epileptic encephalopathies). Severe 5-MTHF depletion (n = 8; range, 0.6-13 nmol/L) was detected in severe MTHF reductase deficiency, Kearns-Sayre syndrome, biotin-responsive striatal necrosis, acute necrotizing encephalitis of Hurst, and FOLR1 defect. A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency. CONCLUSIONS: Of the 2 main forms of cerebral folate deficiency identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5-MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5-MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction.