Paroxysmal Kinesigenic Dyskinesia: First Molecularly Confirmed Case from Africa

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder, with an excellent response to carbamazepine treatment. It has been described in various populations, but not yet in an African population. Case report: In a patient who reported to clinic with side effects of carbamazepine, PRRT2 gene screening was performed based on a clinical history compatible with PKD. A common PRRT2 mutation was identified in this patient, hereby the first genetically confirmed PRRT2-associated PKD in Africa. Discussion: Reporting genetic confirmation of an unusual movement disorder from an equally unusual location shows the wide geographical distribution of PRRT2-associated disease. It also illustrates recognizability of this treatable disorder where the easiest accessible diagnostic tool is neurological history and examination

Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus

Vasopressin regulates body water conservation by redistributing aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical surface of renal collecting ducts, resulting in water reabsorption from urine. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine. Here, we report a frame-shift mutation in AQP2 causing dominant NDI. This AQP2 mutant is a functional water channel when expressed in Xenopus oocytes. However, expressed in polarized renal cells, it is misrouted to the basolateral instead of apical plasma membrane. Additionally, this mutant forms heterotetramers with wild-type AQP2 and redirects this complex to the basolateral surface. The frame shift induces a change in the COOH terminus of AQP2, creating both a leucine- and a tyrosine-based motif, which cause the reversed sorting of AQP2. Our data reveal a novel cellular phenotype in dominant NDI and show that dominance of basolateral sorting motifs in a mutant subunit can be the molecular basis for disease

Genetic characterization of primary lateral sclerosis

BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is a motor neuron disease characterised by loss of the upper motor neurons. Most patients present with slowly progressive spasticity of the legs, which may also spread to the arms or bulbar regions. It is challenging to distinguish between PLS, early-stage amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). The current diagnostic criteria advise against extensive genetic testing. This recommendation is, however, based on limited data. METHODS: We aim to genetically characterize a PLS cohort using whole exome sequencing (WES) for genes associated with ALS, HSP, ataxia and movement disorders (364 genes) and C9orf72 repeat expansions. Patients fulfilling the definite PLS criteria by Turner et al. and with available DNA samples of sufficient quality were recruited from an on-going, population-based epidemiological study. Genetic variants were classified according to the ACMG criteria and assigned to groups based on disease association. RESULTS: WES was performed in 139 patients and the presence of repeat expansions in C9orf72 was analysed separately in 129 patients. This resulted in 31 variants of which 11 were (likely) pathogenic. (Likely) pathogenic variants resulted in 3 groups based on disease association: ALS-FTD (C9orf72, TBK1), pure HSP (SPAST, SPG7), "ALS-HSP-CMT overlap" (FIG4, NEFL, SPG11). DISCUSSION: In a cohort of 139 PLS patients, genetic analyses resulted in 31 variants (22%) of which 10 (7%) (likely) pathogenic associated with different diseases (predominantly ALS and HSP). Based on these results and the literature, we advise to consider genetic analyses in the diagnostic work-up for PLS

Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia

Background Magnesium (Mg2+) is an essential ion for cell growth, neuroplasticity and muscle contraction. Blood Mg2+ levels <0.7 mmol/L may cause a heterogeneous clinical phenotype, including muscle cramps and epilepsy and disturbances in K+ and Ca2+ homeostasis. Over the last decade, the genetic origin of several familial forms of hypomagnesaemia has been found. In 2000, mutations in FXYD2, encoding the γ-subunit of the Na+-K+-ATPase, were identified to cause isolated dominant hypomagnesaemia (IDH) in a large Dutch family suffering from hypomagnesaemia, hypocalciuria and chondrocalcinosis. However, no additional patients have been identified since then. Methods Here, two families with hypomagnesaemia and hypocalciuria were screened for mutations in the FXYD2 gene. Moreover, the patients were clinically and genetically characterized. Results We report a p.Gly41Arg FXYD2 mutation in two families with hypomagnesaemia and hypocalciuria. Interestingly, this is the same mutation as was described in the original study. As in the initial family, several patients suffered from muscle cramps, chondrocalcinosis and epilepsy. Haplotype analysis revealed an overlapping haplotype in all families, suggesting a founder effect. Conclusions The recurrent p.Gly41Arg FXYD2 mutation in two new families with IDH confirms that FXYD2 mutation causes hypomagnesaemia. Until now, no other FXYD2 mutations have been reported which could indicate that other FXYD2 mutations will not cause hypomagnesaemia or are embryonically letha

Respiratory features of centronuclear myopathy in the Netherlands

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 &amp; PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.</p

Genotype-phenotype correlations of KIF5A stalk domain variants

The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D1) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D1 agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D1 agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D1 receptor in motor control

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially