BackgroundPhosphomannomutase deficiency (PMM2-CDG) is the most frequent congenital disorder of glycosylation. The cerebellum is nearly always affected in PMM2-CDG patients, a cerebellar atrophy progression is observed, and cerebellar dysfunction is their main daily functional limitation. Different therapeutic agents are under development, and clinical evaluation of drug candidates will require a standardized score of cerebellar dysfunction. We aim to assess the validity of the International Cooperative Ataxia Rating Scale (ICARS) in children and adolescents with genetically confirmed PMM2-CDG deficiency. We compare ICARS results with the Nijmegen Pediatric CDG Rating Scale (NPCRS), neuroimaging, intelligence quotient (IQ) and molecular data.MethodsOur observational study included 13 PMM2-CDG patients and 21 control subjects. Ethical permissions and informed consents were obtained. Three independent child neurologists rated PMM2-CDG patients and control subjects using the ICARS. A single clinician administered the NPCRS. All patients underwent brain MRI, and the relative diameter of the midsagittal vermis was measured. Psychometric evaluations were available in six patients. The Mann–Whitney U test was used to compare ICARS between patients and controls. To evaluate inter-observer agreement in patients’ ICARS ratings, intraclass correlation coefficients (ICC) were calculated. ICARS internal consistency was evaluated using Cronbach’s alpha. Spearman’s rank correlation coefficient test was used to correlate ICARS with NPCRS, midsagittal vermis relative diameter and IQ.ResultsICARS and ICARS subscores differed between patients and controls (p < 0.001). Interobserver agreement of ICARS was “almost perfect” (ICC = 0.99), with a “good” internal reliability (Cronbach’s alpha = 0.72). ICARS was significantly correlated with the total NPCRS score (rs 0.90, p < 0.001). However, there was no agreement regarding categories of severity. Regarding neuroimaging, inverse correlations between ICARS and midsagittal vermis relative diameter (rs −0.85, p = 0.003) and IQ (rs −0.94, p = 0.005) were found. Patients bearing p.E93A, p.C241S or p.R162W mutations presented a milder phenotype.ConclusionsICARS is a reliable instrument for assessment of PMM2-CDG patients, without significant inter-rater variability. Despite our limited sample size, the results show a good correlation between functional cerebellar assessment, IQ and neuroimagingFor the first a correlation between ICARS, neuroimaging and IQ in PMM2-CDG patients has been demonstrated.

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 AE 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 AE 23.2 vs 40.7 AE 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 View this article online at wileyonlinelibrary.com.

Parasagittal cerebral injury is a specific pathologic lesion that can be found in full-term newborn babies suffering from hypoxic-ischemic encephalopathy. It is defined by the presence of cortical and subcortical white-matter necrosis involving the parasagittal and superomedial areas of the cerebral convexities. We report on two patients who showed parasagittal cerebral injury on magnetic resonance imaging. In both cases antecedents of hypoxic-ischemic encephalopathy were noted. In one of the patients basal ganglia involvement was also detected by cranial magnetic resonance imaging. In the follow-up studies the presence of upper-limb pyramidal signs and dyspraxia were two of the more pronounced symptoms. We will discuss the usefulness of neuroimaging, especially magnetic resonance imaging with coronal views, in the diagnosis of the parasagittal cerebral injury.

The case history of a 3‐year‐old boy without speech and who met 10 criteria of an autistic condition (DSM‐IV) (American Psychiatric Association 1994) is reported. Psychometric evaluation, excluding the verbal scale, resulted in an IQ score of 56. The cytogenetic study showed a 20/22 translocation and an interstitial deletion within the region 22q11: 45, XY, ‐22, +der(20), t(20;22) (q13.3;q11.2), which was confirmed by fluorescence in situ hybridisation (FISH). Although deletions at 22q.11 are responsible for the DiGeorge syndrome; clinical, metabolic, and neurological image studies of the patient were inconsistent with this syndrome. In the clinical examination the patient presented with a mildly dysmorphic facies, pectus excavatum, and a short thumb. A 99mTc HMPAO brain perfusion SPECT showed a hypoperfusion of the left temporoparietal cortex. As there have been no previous reports of autistic patients with abnormalities involving both chromosomes 20 and 22, these findings merit some discussion either as a possible cause of autism or as accompanying factors.

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