Inge Cuppen

De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c–4

Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene‐augmenting therapies.

Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion

Neuraminidase deficiency (mucolipidosis I, sialidosis types I and II, cherry-red spot myoclonus syndrome) is a lysosomal storage disorder with an expanding clinical phenotype. Here, we report the striking diagnostic history of late-onset neuraminidase deficiency in two sisters, currently aged 14 (patient 1) and 15 (patient 2).Patient 1 was referred for evaluation of her vision after a traffic accident. During this examination, nummular cataract, macular cherry-red spot, and optic nerve atrophy were seen. Furthermore, tremors were noticed in her arms and legs. This combination suggested a lysosomal storage disorder. Her family history revealed an older sister, patient 2, who had a long history of unexplained neurologic symptoms; she was under unsuccessful treatment for conversion disorder. Patient 2 showed identical ophthalmological findings. In retrospect, she had presented with avascular osteonecrosis of the right femur head at age 9.Urinary oligosaccharide patterns and enzyme activity revealed neuraminidase deficiency in both patients. Urinary-bound sialic acid levels were normal. Sequencing of NEU1 demonstrated two known compound heterozygous mutations (c.1195_1200dup p.His399_Tyr400dup; c.679G>A, p.Glu227Arg).The substantial time window between onset of typical symptoms and diagnosis in patient 2 suggests inadequate awareness of lysosomal storage disorders among clinicians. Of special interest is the observation that normal urinary sialic acid levels do not exclude neuraminidase deficiency. Urinary oligosaccharide screening is essential to diagnosis in such cases. In addition, patient 2 is the fourth case in the literature with a history of femur head necrosis. Bone defects might therefore be an early manifestation of late-onset neuraminidase deficiency.

Interhemispheric Lipoma, Callosal Anomaly, and Malformations of Cortical Development: A Case Series.

Intracranial lipomas are rare congenital malformations. The most common type of intracranial lipoma is the interhemispheric lipoma, which is frequently associated with callosal anomalies such as hypogenesis or agenesis of the corpus callosum. In contrast, interhemispheric lipomas are less often accompanied with malformations of cortical development (MCD). We report magnetic resonance imaging findings of three infants with an interhemispheric lipoma, associated with a callosal anomaly, and MCD: two infants with nodular interhemispheric lipoma, agenesis of the corpus callosum, and polymicrogyria, and one infant with interhemispheric curvilinear lipoma, hypoplasia of the corpus callosum, and heterotopias. An association was suggested regarding the occurrence of these malformations.

Accuracy of diagnosis and counseling of fetal brain anomalies prior to 24 weeks of gestational age

Abstract Objective: To evaluate the accuracy of prenatal neurosonography in diagnosing underlying causes of fetal ventriculomegaly, posterior fossa anomalies and microcephaly before 24 weeks’ gestational age (GA) and to study the accuracy of prenatal counseling on postnatal prognosis. Methods: A retrospective cohort study based on 146 cases of these fetal brain anomalies before 24 weeks’ GA. Counseling on prognosis was compared with postnatal outcome. Data on genetic testing was analyzed. Results: Out of 146 cases, 135 (92%) were diagnosed correctly before 24 weeks’ GA. Accuracy was 98% (97/99) in cases with multiple anomalies and 81% (38/47) in cases with an isolated abnormality. Counseling on prognosis was correct in 143 out of 146 cases (98%). Prenatal genetic diagnostics detected an anomaly in 51/113 (45%) of cases. In 14/62 (23%) cases prenatal karyotyping was normal, but postnatal array-CGH detected a pathogenic anomaly. Conclusions: Despite the challenges of early gestation, accuracy in diagnosing and counseling fetal brain anomalies before 24 weeks’ GA was high. Prenatal genetic testing is a valuable diagnostic tool and should be offered to all women with fetal brain anomalies. Considering the many different types of anomalies and diverse etiologies, a multidisciplinary approach is essential for counseling on postnatal outcome.

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2–4 (SPACE trial)

Introduction Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA. Methods and analysis We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2–4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events. Ethics and dissemination The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA. Trial registration number NCT02941328.

Expanding the phenotypic spectrum of GABRG2 variants : a recurrent GABRG2 missense variant associated with a severe phenotype

Abstract Pathogenic missense and truncating variants in the GABRG2 gene cause a spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures. In most cases, pathogenic missense variants in the GABRG2 gene segregate with a febrile seizure phenotype. In this case series, we report a recurrent, de novo missense variant (c0.316 G > A; p.A106T) in the GABRG2 gene that was identified in five unrelated individuals. These patients were described to have a more severe phenotype than previously reported for GABRG2 missense variants. Common features include variable early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features and vision/ocular issues. Our report further explores a recurrent pathogenic missense variant within the GABRG2 variant family and broadens the spectrum of associated phenotypes for GABRG2-associated disorders.

Small Biparietal Diameter and Head Circumference Are Part of the Phenotype instead of Independent Prognostic Markers in Fetuses with Spinal Dysraphism

Objective: The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. Methods: BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. Results: BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile. Conclusion: Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome.