De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Phenomenology of abnormal movements in stuttering.

BACKGROUND: Stuttering is often accompanied by involuntary movements, abnormal gestures or changes in facial expression. OBJECTIVE: To describe the incidence and phenomenology of abnormal movements (AMs) in stuttering patients. MATERIALS AND METHODS: Eighty-five consecutive patients with stuttering and 119 normal controls videotaped and subsequently reviewed, in which AMs were classified as voluntary or involuntary, and as concurrent or unrelated to speech. Movement phenomenology was correlated with disease severity. RESULTS: Of 85 stuttering patients studied, 51.7% had AMs and 22 more than one AM. Sixty-six different AMs were identified, of which 83.3% occurred during speech, 72.7% were classified as involuntary, and 27.2% as voluntary. Of 38 involuntary movements concurrent to speech, 25 were originally perceived as voluntary, but had since become involuntary through repeated use during stuttering. All involuntary movements not concurrent to speech fulfilled criteria for tics. CONCLUSION: AMs occurring during stuttering were not always involuntary; movements not concurrent with speech clearly fulfilled clinical criteria for tics and were similar in incidence to normal controls. Inverse correlation was found between conscious control of movement during speech and stuttering severity. Many involuntary movements occurring during speech were clearly referred by patients as initially voluntary early on in the development of their speech disorder (starters or unblockers), underlining the importance of repetitive use of complex motor sequences as a source for putative involuntary movement genesis.

Neuronal MDR-1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy.

SUMMARY: It is estimated that 20-25% of epileptic patients fail to achieve good control with antiepileptic drug (AED) treatment; thus, refractory epilepsy (RE) has been described in patients who have adequate therapeutic levels of AEDs without control of seizures. Multidrug resistance genes have been reported to be highly expressed in brain of patients with RE. Persistent low plasma levels of AEDs and high brain expression of the multidrug resistance product P-glycoprotein (P-gp) have been previously communicated in a case report of RE secondary to tuberous sclerosis. Here, the authors report a case of an 8-year-old boy diagnosed with partial RE with focal seizures who was admitted to hospital for a severe episode of subintrant crisis. The patient received polytherapy with carbamazepine (CBZ), phenytoin (PHT), and valproic acid (VA); however, habitual doses of these AEDs failed to control the patient's symptoms. AED blood levels were monitored for 25 consecutive days and showed low values in 8/25 (33%) for CBZ, 10/25 (40%) for PHT, and 25/25 (100%) for VA of samples studied. Because the patient developed focal status epilepticus, surgical treatment by callosotomy was done, resulting in a significant improvement in epileptic symptoms. The immunostaining of brain specimens showed significantly increased expression of P-gp not only in vascular endothelial cells and related astrocytes but also in neurons. Overexpression of P-gp in the brain does not explain the low blood levels of AEDs described in these cases. Different mechanisms such as drug-drug interactions and drug transporters can be involved in the results observed. The P-gp overexpression and/or its pharmacologic induction should be considered as a potential mechanism responsible for drug resistance to epilepsy treatment and highly suspected in patients with persistent subtherapeutic AEDs plasma levels.