Jul 2026· Movement Disorders Clinical Practice· 0 citations· 18 references
Medicine
TL;DR
The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression and should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.
Abstract
Background
Biallelic variants in DNAJC6 cause PARK-DNAJC6 (historically referred to as PARK19), a rare autosomal recessive juvenile-onset dystonia-parkinsonism syndrome. Neurodevelopmental delay or regression, epilepsy, movement disorders, and psychiatric symptoms are also present. Progression is fast with frequent bulbar, gastrointestinal involvement and early loss of ambulation.
CASES
We report two siblings (17 and 14 years) harboring a novel homozygous nonsense variant in DNAJC6, p.Cys325*, not previously described in the medical literature and absent from population databases. The variant is predicted to truncate the protein, supporting a loss-of-function mechanism consistent with the gene's disease biology. Both patients exhibited developmental regression, parkinsonism with dystonia, cognitive decline, dysphagia, and marked sialorrhea, with severe, accelerated functional deterioration. Levodopa produced only mild benefit; in the older sibling, dose escalation provoked an adverse reaction with sustained upgaze/ophthalmoparesis, opisthotonus, and hypertension.
LITERATURE REVIEW
We found 23 previously reported DNAJC6 patients, most with early-onset parkinsonism with variable levodopa responsiveness, frequent developmental and psychiatric comorbidity, and prominent bulbar features.
Conclusions
The novel DNAJC6 p.Cys325* variant is associated with severe, early-onset parkinsonism and developmental regression. DNAJC6 should be considered in children and adolescents presenting with parkinsonism plus neurodevelopmental decline, particularly when levodopa benefit is modest, and dose-related adverse motor crises occur.
This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.
Rina Su, Lei Zhu, Lin Jiang et al.· Frontiers in Neuroscience· 0 citations
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.
Ali Nikkhah, R. Badv, S. Habibi et al.· Case Reports in Neurological...· 0 citations
Background: Gordon Holmes syndrome (GHS) is a rare genetic disorder, usually manifesting as a broad spectrum of neurological symptoms and hypogonadotropic hypogonadism. Only a limited number of cases presenting this congenital disorder have been reported in the literature. Since the genetic and phenotypic heterogeneity of GHS, it is crucial to report novel cases.
Case presentation: Here we report a novel homozygous missense variant in RNF216 gene c.1055T>G (p.(Phe352Cys)) in three siblings. Primary concerns were absence of secondary sexual characteristics, and amenorrhea occurred among female patients. Based on laboratory test results and clinical features, hypogonadotropic hypogonadism was diagnosed. Neurological examination revealed no signs of ataxia in siblings. However, brain magnetic resonance imaging revealed pronounced changes in the cerebral white matter for female patients. Due to primary amenorrhea and the absence of secondary sexual characteristics, treatment was initiated. Treatment might be adjusted in the presence of fertility considerations.
Conclusions: This case contributes to the limited knowledge of GHS and highlights the importance of hypogonadotropic hypogonadism treatment and close observation of neurological symptoms that may develop over time.
BackgroundKaya-Barakat-Masson syndrome (KABAMAS) is a recently described autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in YIF1B, a gene crucial for trafficking between the endoplasmic reticulum and the Golgi apparatus. Disruption of this pathway leads to Golgi disorganization and neuronal dysfunction, resulting in severe developmental delay, visual impairment, and progressive spasticity.Case PresentationWe report an 11-month-old Turkish girl with profound developmental delay, absent head control, poor feeding, laryngomalacia and cortical visual impairment. Brain magnetic resonance imaging (MRI) revealed corpus callosum thinning and mild ventriculomegaly. Comprehensive metabolic investigations were unrevealing. Whole exome sequencing analysis identified a novel homozygous YIF1B frameshift variant, c.440_441delinsA (p.Ala147Aspfs*51), predicted to cause loss of function.ConclusionThis case broadens the mutational spectrum of YIF1B-related disease and highlights the distinctive clinical pattern of KABAMAS. Recognition of the combination of developmental delay, cortical visual loss, and normal metabolic studies should prompt early genetic analysis. Timely molecular diagnosis enables accurate counseling and multidisciplinary management for affected families.
Sabire Gokalp, A. Olgaç, Fehime Erdem Karapınar et al.· Journal of Child Neurology· 0 citations
BackgroundTANGO2-related disorder (TDD) is a rare autosomal recessive condition characterized by episodic metabolic crises, rhabdomyolysis, encephalopathy, and life-threatening cardiac arrhythmias, with marked phenotypic variability that often contributes to delayed diagnosis.Case presentationWe report 2 sisters homozygous for the recurrent TANGO2 variant c.460G>A (p.Gly154Arg), identified in a family of Hispanic/Latino ancestry, who exhibited divergent clinical presentations. The older sibling presented with developmental delay and recurrent fasting-induced hypoglycemia associated with hyperCKemia and episodic weakness, whereas the younger sibling showed early hypotonia, ataxia, behavioral dysregulation, and subclinical hypothyroidism without initial metabolic crises. Brain magnetic resonance imaging studies were normal in both patients. In both cases, routine metabolic testing was largely unremarkable between episodes, and early manifestations were interpreted within isolated subspecialty frameworks, delaying diagnostic integration.ConclusionThese cases highlight intrafamilial variability within the recognized TDD spectrum and underscore the importance of early recognition of neurologic and endocrine features as potential red flags. Prompt molecular diagnosis is essential to guide anticipatory management and reduce morbidity and mortality.
Diego Armando Nájera-Eguía, Estefanía Villarreal-Garza, L. Martínez-de-Villarreal et al.· Journal of Child Neurology· 0 citations