AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG).

OBJECTIVE: Phosphomannomutase deficiency (PMM2 congenital disorder of glycosylation [PMM2-CDG]) causes cerebellar syndrome and strokelike episodes (SLEs). SLEs are also described in patients with gain-of-function mutations in the CaV2.1 channel, for which acetazolamide therapy is suggested. Impairment in N-glycosylation of CaV2.1 promotes gain-of-function effects and may participate in cerebellar syndrome in PMM2-CDG. AZATAX was designed to establish whether acetazolamide is safe and improves cerebellar syndrome in PMM2-CDG. METHODS: A clinical trial included PMM2-CDG patients, with a 6-month first-phase single acetazolamide therapy group, followed by a randomized 5-week withdrawal phase. Safety was assessed. The primary outcome measure was improvement in the International Cooperative Ataxia Rating Scale (ICARS). Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PATA test), and cognitive scores. RESULTS: Twenty-four patients (mean age = 12.3 ± 4.5 years) were included, showing no serious adverse events. Thirteen patients required dose adjustment due to low bicarbonate or asthenia. There were improvements on ICARS (34.9 ± 23.2 vs 40.7 ± 24.8, effect size = 1.48, 95% confidence interval [CI] = 4.0-7.6, p < 0.001), detected at 6 weeks in 18 patients among the 20 responders, on NPCRS (95% CI = 0.3-1.6, p = 0.013) and on the PATA test (95% CI = 0.5-3.0, p = 0.006). Acetazolamide improved prothrombin time, factor X, and antithrombin. Clinical severity, epilepsy, and lipodystrophy predicted greater response. The randomized withdrawal phase showed ICARS worsening in the withdrawal group (effect size = 1.46, 95% CI = 2.65-7.52, p = 0.001). INTERPRETATION: AZATAX is the first clinical trial of PMM2-CDG. Acetazolamide is well tolerated and effective for motor cerebellar syndrome. Its ability to prevent SLEs and its long-term effects on kidney function should be addressed in future studies. Ann Neurol 2019;85:740-751.

[Developmental amnesia as a focal cognitive sequela of a neonatal pathology]. / Amnesia del desarrollo como secuela cognitiva focal de patologia neonatal.

INTRODUCTION: The developmental amnesia is a recently known entity that occurs as a consequence of hypoxic-ischemic events in the perinatal period. This is a specific deficit of episodic memory with greater preservation of semantic memory and other memory components such as the immediate and working memory. It occurs in patients without apparent neurological sequelae, with normal psychomotor development and general intelligence. The developmental amnesia has been associated with bilateral involvement of the hippocampus, which is evident in some cases on magnetic resonance imaging (MRI) as signal disturbance and signs of atrophy, or reduced size of the hippocampus in brain volumetric studies. PATIENTS AND METHODS: We present six observations of developmental amnesia, their clinical, neuropsychological and neuroimaging findings. RESULTS: All of them show impaired episodic memory with preservation of semantic memory, have a normal general intelligence and follow a regular school with special educational needs. CONCLUSIONS: It is necessary to keep in mind this entity in monitoring risk newborns by their perinatal history and include the exploration of memory in neuropsychological study of these subjects. On the other hand, we highlight the specificity of the clinical and neuropsychological profile for the diagnosis of developmental amnesia even in the absence of hippocampal lesions on conventional MRI.