Aug 2026· Movement Disorders· 0 citations· 25 references
Medicine
TL;DR
It is demonstrated that both heterozygous MCOLN1 variants impair TRPML1 function in vitro, identifying MCOLN1 as a candidate gene for α-synucleinopathies that warrants further investigation in larger cohorts.
Abstract
Background
Growing evidence links lysosomal dysfunction to parkinsonism. TRPML1, a lysosomal cation channel encoded by the MCOLN1 gene, is essential for lysosomal function. Biallelic loss-of-function variants in MCOLN1 cause mucolipidosis type IV. However, the role of heterozygous MCOLN1 variants remains unclear.
Methods
Two patients with α-synucleinopathies underwent clinical evaluation and whole-genome sequencing. The functional effects of TRPML1 variants were assessed using immunofluorescence, lysosomal patch-clamp recording, and autophagic flux assay.
Results
Two heterozygous MCOLN1 variants were identified: p.E376K in a patient with multiple system atrophy and p.L315del in a patient with early-onset Parkinson's disease. Functional analyses showed that p.L315del disrupted lysosomal localization, and both variants significantly reduced lysosomal currents upon TRPML1 agonist stimulation, with a trend toward impaired autophagic flux, indicating loss of function.
The first functional characterization of the cardiomyopathy-associated SMYD1 N101S variant identified in a child with severe infantile cardiomyopathy is provided, establishing a mechanistic link between SMYD1 dysfunction and infantile cardiomyopathy and highlighting the importance of integrating genomic and functional approaches in rare cardiovascular disease.
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Findings support a dose-dependent SLC20A2 disease spectrum and expand the phenotype associated with biallelic loss of function from primary brain calcification toward severe early-onset neurodevelopmental disorder with prominent vascular and leptomeningeal calcification.
Mehmet Burak Mutlu, Abdullah Sezer, Elif Özdemir et al.· Journal of Human Genetics· 0 citations
Parkinsonism–dystonia Type 2 (PKDYS2) is a rare autosomal recessive disorder caused by SLC18A2 variants affecting the vesicular monoamine transporter 2 (VMAT2). We report the first genetically confirmed Iranian patient, an 18‐month‐old boy presenting with profound developmental delay, axial hypotonia, limb hypertonia, dystonia, oculogyric crises, ptosis, and autonomic dysfunction. Brain MRI, metabolic studies, and neurophysiological evaluations were normal. Whole‐exome sequencing identified a novel homozygous canonical splice‐site variant in SLC18A2 (NM_003054.6:c.1071‐2A > G), confirmed by Sanger sequencing and absent from population databases. SpliceAI predicted loss of the native splice acceptor site (DS_AL = 0.74), supporting a deleterious effect on RNA splicing. According to ACMG criteria, the variant was classified as likely pathogenic. Levodopa–benserazide failed to provide sustained benefit and caused irritability and insomnia, whereas pramipexole produced modest improvement in bradykinesia, ptosis, and sweating with persistence of dystonia and oculogyric crises. Comparison with reported international cases shows a consistent phenotype and limited therapeutic response. This case expands the mutational spectrum of SLC18A2‐related disease and highlights the importance of early genetic diagnosis.
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Mazhor Aldosary, Hanan Alqudairy, Nourah Alshalan et al.· International Journal of Mol...· 0 citations
Heterozygous pathogenic variants in the
KCNQ2
gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The
KCNQ2
gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant
KCNQ2
p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant.
Here, we report a family with two adult carriers of the heterozygous
KCNQ2
p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed.
Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life.
These findings challenge the concept of
KCNQ2
p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.
P. Christova, M. Ostrožovičová, J. Neupauerová et al.· BMC Neurology· 0 citations
Findings support a potential link between mitochondrial dysfunction, enteric neurodegeneration, and idiopathic achalasia and rare mitochondrial-related variants may contribute to disease susceptibility in selected individuals by increasing vulnerability of inhibitory enteric neurons, although functional validation and larger studies are required.
A. Latiano, F. Tavano, L. Micale et al.· International Journal of Mol...· 0 citations