Anne Roubergue

Dystonia and parkinsonism in GM1 type 3 gangliosidosis.

GM1 gangliosidosis is due to β‐galactosidase deficiency. Only patients with type 3 disease survive into adulthood and develop movement disorders. Clinical descriptions of this form are rare, particularly in non‐Japanese patients. We describe four new patients and systematically analyze all previous reports found by a literature search and contacts with the authors for additional information. Generalized dystonia remained the predominant feature throughout the disease course and was often associated with akinetic–rigid parkinsonism. GM1 gangliosidosis must be considered as a cause of early‐onset generalized dystonia, particularly in patients with short stature and skeletal dysplasia.

Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin‐1A

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv7.2 (KCNQ2; Q2) and Kv7.3 (KCNQ3; Q3) voltage‐dependent K+ channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug‐resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression‐burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named “KCNQ2 encephalopathy.” In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin‐1A, highlighting a novel pathogenetic mechanism for KCNQ2‐related epilepsies.

Recessive hereditary methaemoglobinaemia, type II: delineation of the clinical spectrum

Type II recessive hereditary methaemoglobinaemia (RHM) is a rare disease due to generalized NADH-cytochrome b5 reductase (cytb5r) deficiency. It results in mild cyanosis and severe neurological impairment. The clinical features and long-term outcome are poorly documented, and there are no systematic reviews. We examined six cases of type II RHM, four of which were new, together with 45 previously published cases, in order to establish the range of phenotypic expression. The clinical picture was very similar in most cases, with severe encephalopathy, microcephaly, generalized dystonia, movement disorders and mild cyanosis. The neurological prognosis was poor; in particular, none of the patients walked or spoke. In addition, the possibility of an atypical and milder phenotype was considered. We concluded that children with unexplained severe encephalopathy associated with generalized dystonia should be examined for cyanosis and have a methaemoglobinaemia assay performed. The diagnosis can be confirmed by very low cytb5r activity in both red and white blood cells. Here we report three novel mutations in the NADH-cytochrome b5 reductase gene. Prenatal diagnosis of this extremely severe disease should be proposed to affected families.

The multiple faces of the ATP1A3-related dystonic movement disorder

Alternating hemiplegia of childhood (AHC) and rapidonset dystonia-parkinsonism (RDP/DYT12) are 2 rare disorders caused by dominant mutations in ATP1A3 encoding the neuron-specific Na/K-ATPase a3 subunit. AHC is characterized by episodes of alternating hemiplegia/quadriplegia and dystonic or tonic attacks that are associated with permanent neurological deficits including intellectual disability and movement disorders. Paroxysmal events typically start before 18 months of age and are often precipitated by specific triggers. RDP is characterized by abrupt onset of dystonia within hours to weeks, associated with parkinsonism. Onset can be precipitated by triggers similar to AHC and usually occurs in adolescence or early adulthood. None of the ATP1A3 mutations detected in AHC (n 5 26) was reported in RDP (n 5 11), suggesting that AHC and RDP are allelic disorders due to mutations with distinct effects on ATP1A3 activity. Nevertheless, some overlap exists because permanent dystonia is found in most AHC patients and is a core feature of RDP, and paroxysmal dystonia is frequent in AHC cases and is sometimes observed in RDP. We studied a single family with 4 affected subjects over 3 generations who display typical as well as atypical AHC (Supplemental Fig. 1). Their neurological manifestations are detailed in Table 1. One video shows the mild permanent symptoms of patient III-2. Sequencing ATP1A3 showed the heterozygous substitution c.2767G>A in exon 20 (p.Asp923Asn) in the 4 symptomatic patients (Supplemental Fig. 1). The mutation occurred de novo, then segregated with the disease in over 3 generations. Interestingly, this mutation was previously reported in 2 unrelated patients with RDP. We further characterized the phenotypes resulting from the p.Asp923Asn mutation, considering the 4 cases reported here and the 2 patients with RDP previously reported (see Table 1). Four patients had AHC (typical, n 5 1; atypical, n 5 3), and 2 patients had RDP (typical, n 5 1; atypical, n 5 1). Interestingly, paroxysmal exerciseinduced dystonia in the absence of plegic attacks was the main manifestation after childhood in the 3 adult patients of the reported family. If this feature has never been reported in RDP, it has been observed in some isolated cases of AHC. Our observation that the ATP1A3 p.Asp923Asn mutation results in typical AHC, typical RDP, and variant phenotypes suggests that these clinical syndromes represent different expressions of the same disorder. This challenges the hypothesis of a mechanistically distinct functional effect of AHCand RDP-causing mutations. ATP1A3 mutations alter the Na/K ATPase pump’s activity in different ways. AHCcausing mutations were reported to not reduce protein expression in contrast with most of the RDP-causing mutations. However, the p.Asp923Asn substitution was 1 of the 3 RDP-causing mutations affecting ATP1A3 activity without modifying protein expression, thereby having an effect apparently similar to AHC-causing mutations at the cellular level. Our findings emphasize that the ATP1A3 mutation is not the sole determinant of clinical expression, implying that genetic, epigenetic, and environmental factors play an important role in the clinical expression of ATP1A3-related disease.

Rett syndrome: An overlooked diagnosis in women with stereotypic hand movements, psychomotor retardation, Parkinsonism, and dystonia?

Rett syndrome is an X‐linked neurodevelopmental disorder resulting in profound psychomotor retardation. It is usually diagnosed by a pediatrician or pediatric neurologist. Adult neurologists may, therefore, overlook the possibility of Rett syndrome in women with psychomotor retardation of unknown etiology. We report the case of a woman diagnosed with Rett syndrome at age 49 years. This report emphasizes the diagnostic value of movement disorders, including hand stereotypies, Parkinsonism, and dystonia, in adults with Rett syndrome.

Excellent Response to a Ketogenic Diet in a Patient with Alternating Hemiplegia of Childhood

UNLABELLED Alternating hemiplegia of childhood (AHC) is a rare disorder caused by heterozygous mutations in ATP1A3. AHC is associated with early-onset plegic and tonic/dystonic attacks and permanent neurologic deficits. Attacks tend to persist through life. Flunarizine therapy occasionally reduces the severity, duration and frequency of attacks. A ketogenic diet/modified Atkins diet (KD/MAD) can attenuate paroxysmal movement disorders associated with GLUT1 deficiency syndrome (GLUT1DS), but there are no reports on the effect of KD/MAD in AHC. We describe the case of a young girl with AHC who had tonic/dystonic and plegic attacks, mostly triggered by exercise, together with mild permanent dystonia and mental retardation. Her family had a history of dominant (three affected generations) paroxysmal exercise-induced dystonia. A history of plegic attacks that ceased after childhood was retraced from the medical records of the three affected adults, leading to the diagnosis of familial AHC due to ATP1A3 p.Asp923Asn mutation (Roubergue et al 2013). KD/MAD was considered for the proband when she was 3½ years old, following initial misdiagnosis of GLUT1DS. MAD, a KD variant, was chosen because it is easier to manage than KD and is similarly effective to KD in most GLUT1DS patients. MAD resulted in complete disappearance of the attacks during 15 months of follow-up. CONCLUSIONS A modified Atkins diet had a sustained beneficial effect on attacks associated with AHC. Although preliminary, this observation suggests that a ketogenic diet might be a therapeutic option for paroxysmal disorders in some patients with alternating hemiplegia of childhood.

Dystonic tremor caused by mutation of the glucose transporter gene GLUT1

Glucose transporter 1 deficiency syndrome (GLUT1-DS) is due to heterozygous mutation of the glucose transporter type 1 gene (GLUT1/SLC2A1). GLUT1-DS is characterized by movement disorders, including paroxysmal exercise-induced dystonia (PED), as well as seizures, mental retardation and hypoglycorrhachia. Tremor was recently shown to be part of the phenotype, but its clinical and electrophysiological features have not yet been described in detail, and GLUT1 tremor reports are rare. We describe two patients, a young woman and her mother, who were referred to us for tremor. We also systematically review published cases of GLUT1-DS with tremor (14 cases, including ours), focusing on clinical features. In most cases (10/14), the tremor, which involved the limbs and voice, fulfilled clinical criteria for dystonic tremor (DT), occurring in body areas affected by dystonia. Tremor was the only permanent symptom in 2 cases. Recordings, reported here for the first time, showed an irregular 6- to 8.5-Hz tremor compatible with DT in our two patients. These findings show that tremor, and particularly DT, may be a presenting symptom of GLUT1-DS. Patients who present with dystonic tremor, with or without mental retardation, seizures, movement disorders and/or a family history, should therefore be screened for GLUT1-DS.

Long-Term Follow-Up and Adult Outcome of 6-Pyruvoyl- Tetrahydropterin Synthase Deficiency

Little information is available on the long‐term course and adult outcome of patients with 6‐pyruvoyl‐tetrahydropterin synthase (PTPS) deficiency. We describe the course of a 32‐year‐old woman with hypotonia, dystonia, choreoathetosis, mental retardation, behavioral disturbances, and incomplete puberty due to PTPS deficiency. From the age of 6 months she developed progressive hypotonia and choreoathtetoid movements despite good control of hyperphenylalaninemia. Tetrahydrobiopterin deficiency was diagnosed at age 3 years. She had a dramatic response to L‐dopa, which persisted at a stable dose for 29 years. Reducing the L‐dopa dose led to severe axial hypotonia and limb dystonia, and increasing it led to florid abnormal movements and behavioral disorders. This report illustrates the role of dopamine modulation in motor, psychiatric, and endocrine functions.

Myoclonus and generalized digestive dysmotility in triple A syndrome with AAAS gene mutation

We report on the case of a 25‐year‐old woman with triple A syndrome and gene mutation, who, during the long follow‐up period of 23 years, developed myoclonus of the face and the upper limbs (with normal brain magnetic resonance spectroscopy) and widespread digestive dysmotility, involving small bowels and gall bladder. These features, not previously described, illustrate an extension of the cerebral and digestive neurological involvement in this syndrome.

Déficience intellectuelle et environnement : contribution des courbes de croissance au diagnostic étiologique

Although deprived environment is known for more than 50 years to be one of the etiology of mental retardation in infancy, this remains unrecognized by many paediatricians and family practitionners. Yet if appropriate therapeutic measures are instituted early enough, future development of the child is good. A study of the growth curves in relation with the environmental changes, can help to diagnose environmental mental retardation. As an illustration, we present the cases of 5 children first addressed for developmental delay, and secondly removed from their usual environment for psychosocial reasons. Mean duration of follow-up was 10 years, including at least 5 years after the removal. All 5 children had non-organic failure to thrive which was displayed only on the retrospective study of their records. Four recovered from their developmental retardation.