Non-progressive Cerebellar Ataxia Research Articles

A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia.

VLDLR cerebellar hypoplasia is characterized by intellectual disability, non-progressive cerebellar ataxia, and seizures. The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem. Biallelic VLDLR pathogenic variants cause loss-of-function of the encoded very low-density lipoprotein receptor. VLDLR exons 4 and 16 are alternatively spliced, resulting in the expression of four transcript variants, including two exon 4-lacking mRNAs expressed in the human brain. Previously reported VLDLR pathogenic variants affect all four transcript variants. Here we report on two sisters with facial dysmorphism, microcephaly, intellectual disability, and normal brain imaging. Exome sequencing in one patient identified the homozygous VLDLR nonsense variant c.376C>T; p.(Gln126*) in exon 4; her similarly affected sister also carried the homozygous variant and parents were heterozygous carriers. VLDLR transcript analysis identified mRNAs with and without exon 4 in patient fibroblasts, while exon 4-containing VLDLR mRNAs were predominantly detected in control fibroblasts. We found significantly reduced VLDLR mRNA levels in patient compared to control cells, likely caused by nonsense-mediated mRNA decay of exon 4-containing VLDLR transcripts. Expression of neuronal VLDLR isoforms produced from exon 4-lacking transcripts may have protected both patients from developing the cerebellar hypoplasia phenotype.

PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology.

The PMPCA gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum changes were found in severe cases. The patient was diagnosed using whole exome sequencing. Skin fibroblasts were used for confirmation of α-MPP levels using western blot and mitochondrial morphology assessment of immunofluorescent confocal microscopy images. Two novel compound heterozygous variants in the PMPCA gene (p.Tyr241Ser and p.Met251Val) were identified in an 8-year-old proband with progressive spastic quadriparesis, delayed psychomotor development, and intellectual disability, with onset at 13 months. The brain imaging showed cortical and cerebellar atrophy, reduced volume of basal ganglia with striatum hyperintensity, and periventricular white matter changes. The patient's fibroblasts showed a decreased α-MPP level and reduced and fragmented mitochondria. The described case contributes to the number of patients with progressive PMPCA-related disease with a severe intermediate phenotype. Moreover, we extend the phenotype to Leigh-like white matter changes that have not been described in previously reported cases.

New Insights into the Neuropsychological Profile and Intellectual Quotient Variability in Joubert Syndrome Compared to Other Congenital Cerebellar Malformations.

The neuropsychological characteristics of the cerebellar cognitive affective syndrome (CCAS) in congenital, non-progressive malformations of the cerebellum have been scarcely investigated, and even less is known for Joubert syndrome (JS), an inherited, non-progressive cerebellar ataxia characterized by the so-called molar tooth sign. The few studies on this topic reported inconsistent results about intellectual functioning and specific neuropsychological impairments. The aim of this research is to examine the neuropsychological profile of JS compared to other congenital cerebellar malformations (CM), considering individual variability of intellectual quotient (IQ) in the two groups. Fourteen patients with JS and 15 patients with CM aged 6-25 years were tested through a comprehensive, standardized neuropsychological battery. Their scores in the neuropsychological domains were inspected through descriptive analysis and compared by mean of MANOVA and ANOVA models, then replicated inserting IQ as covariate. The two groups showed a largely overlapping neuropsychological profile, consistent with CCAS. However, the JS group showed worse performance in visual-spatial memory compared to CM patients, although this difference was mitigated when considering IQ. These findings highlight a divergence between JS and other CM in visual-spatial memory, which might suggest a critical role of the cerebellum in recalling task-relevant memories and might inform rehabilitative interventions.

Pediatric Slow-Progressive, but Not Non-Progressive Cerebellar Ataxia Delays Intra-Limb Anticipatory Postural Adjustments in the Upper Arm.

We recently investigated the role of the cerebellum during development, reporting that children with genetic slow-progressive ataxia (SlowP) show worse postural control during quiet stance and gait initiation compared to healthy children (H). Instead, children with genetic non-progressive ataxia (NonP) recalled the behavior of H. This may derive from compensatory networks, which are hindered by disease progression in SlowP while free to develop in NonP. In the aim of extending our findings to intra-limb postural control, we recorded, in 10 NonP, 10 SlowP and 10 H young patients, Anticipatory Postural Adjustments (APAs) in the proximal muscles of the upper-limb and preceding brisk index finger flexions. No significant differences in APA timing occurred between NonP and H, while APAs in SlowP were delayed. Indeed, the excitatory APA in Triceps Brachii was always present but significantly delayed with respect to both H and NonP. Moreover, the inhibitory APAs in the Biceps Brachii and Anterior Deltoid, which are normally followed by a late excitation, could not be detected in most SlowP children, as if inhibition was delayed to the extent where there was overlap with a late excitation. In conclusion, disease progression seems to be detrimental for intra-limb posture, supporting the idea that inter- and intra-limb postures seemingly share the same control mechanism.

Phenotypic spectrum of patients with Poretti-Boltshauser syndrome: Patient report of antenatal ventriculomegaly and esophageal atresia

Poretti-Boltshauser syndrome (PTBHS) is an autosomal recessive disorder characterized by cerebellar dysplasia with cysts and an abnormal shape of the fourth ventricle on neuroimaging, due to pathogenic variants in the LAMA1 gene. The clinical spectrum mainly consists of neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements and retinal dystrophy.We report a patient presenting with ventriculomegaly on antenatal neuroimaging and a neonatal diagnosis of Type III esophageal atresia. She subsequently developed severe myopia and strabismus with retinal dystrophy, mild developmental delay, and cerebellar dysplasia. Genetic investigations confirmed PTBHS.This report confirms previous reports of antenatal ventriculomegaly in PTBHS patients and documents a so far unreported occurrence of esophageal atresia in PTBHS. We additionally gathered phenotype and genotype descriptions of published cases in an effort to better define the spectrum of PTBHS.

Adult onset cerebellar ataxia due to novel mutations in BRAT1

BRAT 1 (BRCA1-associated ATM activator 1) variants were first reported in 2012 in newborns with lethal neonatal rigidity and multifocal seizure syndrome (RMFSL). They have also been associated with early onset neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS). More recently a milder phenotype characterized by nonprogressive cerebellar ataxia (NPCA) has been reported. We describe the case of a 66 year old woman with sporadic cerebellar ataxia, spasticity and mental retardation in whom we detected two novel mutations in BRAT1.

Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease

Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition.

Clinical phenotypes of infantile onset CACNA1A-related disorder.

CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations. This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BackgroundCerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early‐onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non‐progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.MethodsFollowing the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR‐based Sanger sequencing.ResultsA novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand‐binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP‐binding domain.ConclusionOur findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype‐phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.

Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation.

ObjectiveTo describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome.MethodsWe studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an AIFM1 variant identified by CES and demonstrate its pathogenicity.ResultsThe proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the AIFM1 gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance.ConclusionsOur report extends the molecular and phenotypic spectrum of AIFM1 mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.

Spinocerebellar Ataxia type 29 in a family of M\u0101ori descent

BackgroundMutations in the Inositol 1,4,5-Trisphosphate Receptor Type 1 (ITPR1) gene cause spinocerebellar ataxia type 29 (SCA29), a rare congenital-onset autosomal dominant non-progressive cerebellar ataxia. The Māori, indigenous to New Zealand, are an understudied population for genetic ataxias.Case presentationWe investigated the genetic origins of spinocerebellar ataxia in a family of Māori descent consisting of two affected sisters and their unaffected parents. Whole exome sequencing identified a pathogenic variant, p.Thr267Met, in ITPR1 in both sisters, establishing their diagnosis as SCA29.ConclusionsWe report the identification of a family of Māori descent with a mutation causing SCA29, extending the worldwide scope of this disease. Although this mutation has occurred de novo in other populations, suggesting a mutational hotspot, the children in this family inherited it from their unaffected mother who was germline mosaic.

Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia.

ObjectiveTo investigate the pathogenicity of a novel homozygous BRAT1 variant in 2 siblings with nonprogressive cerebellar ataxia (NPCA) through functional studies on primary and immortalized patient cell lines.MethodsBRAT1 protein levels and ataxia-telangiectasia mutated (ATM) kinase activity in patient-derived and control cell lines were assessed by Western blotting. The impact of the novel BRAT1 variants on mitochondrial function was also assessed, by comparing patient and control cell lines for rates of oxygen consumption and for phosphorylation (S293) of the E1⍺ subunit of pyruvate dehydrogenase (PDH).ResultsTwo male siblings with NPCA, mild intellectual disability, and isolated cerebellar atrophy were found to be homozygous for a c.185T>A (p.Val62Glu) variant in BRAT1 by whole exome sequencing. Western blotting revealed markedly decreased BRAT1 protein levels in lymphocytes and/or fibroblast cells from both affected siblings compared to control cell lines. There were no differences between the patient and control cells in ATM kinase activation, following ionizing radiation. Mitochondrial studies were initially suggestive of a defect in regulation of PDH activity, but there was no evidence of increased phosphorylation of the E1⍺ subunit of the PDH complex. Measurement of oxygen consumption rates similarly failed to identify differences between patient and control cells.ConclusionsBiallelic pathogenic variants in BRAT1 can be associated with NPCA, a phenotype considerably milder than previously reported. Surprisingly, despite the molecular role currently proposed for BRAT1 in ATM regulation, this disorder is unlikely to result from defective ATM kinase or mitochondrial dysfunction.

Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features

BackgroundGillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka.Case presentationA 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene.ConclusionThe report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members.

Identification of a Splicing Mutation in ITPR1 via WES in a Chinese Early-Onset Spinocerebellar Ataxia Family

Mutations in the inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) lead to SCA15, SCA16, and SCA29. To date, only a few families with SCA29 have been reported. A three-generation Chinese family including four affected persons and two unaffected persons were enrolled in this study. We conducted whole-exome sequencing (WES) of the proband DNA initially to find the causal gene. We ascertained the family with autosomal dominant type of congenital nonprogressive cerebellar ataxia (CNPCA) associated with delayed motor and cognitive impairment. WES study was performed with two patients and identified c.1207-2A–T transition, in exon 14 of ITPR1, which was a splicing mutation. Sanger sequencing showed that four patients within this family carried the mutation and two unaffected members did not carry it. The results showed that the novel splicing mutation of ITPR1 was the causative gene for SCA29. In conclusion, we identified a novel SCA29 causative splicing mutation of ITPR1 in a Chinese family. We suggest ITPR1 gene analysis shall be a priority for diagnosis of patients with early-onset CNPCA. Our study demonstrated that whole-exome sequencing might rapidly improve the diagnosis of genetic ataxias.

Mutational analysis of ITPR1 in a Taiwanese cohort with cerebellar ataxias.

BackgroundThe inositol 1,4,5-triphosphate (IP3) receptor type 1 gene (ITPR1) encodes the IP3 receptor type 1 (IP3R1), which modulates intracellular calcium homeostasis and signaling. Mutations in ITPR1 have been implicated in inherited cerebellar ataxias. The aim of this study was to investigate the role of ITPR1 mutations, including both large segmental deletion and single nucleotide mutations, in a Han Chinese cohort with inherited cerebellar ataxias in Taiwan.Methodology and principal findingsNinety-three unrelated individuals with molecularly unassigned spinocerebellar ataxia selected from 585 pedigrees with autosomal dominant cerebellar ataxias, were recruited into the study with elaborate clinical evaluations. The quantitative PCR technique was used to survey large segmental deletion of ITPR1 and a targeted sequencing approach was applied to sequence all of the 61 exons and the flanking regions of ITPR1. A novel ITPR1 mutation, c.7721T>C (p.V2574A), was identified in a family with dominantly inherited cerebellar ataxia. The proband has an adult-onset non-progressive pure cerebellar ataxia and her daughter is afflicted with a childhood onset cerebellar ataxia with intellectual sub-normalities.ConclusionITPR1 mutation is an uncommon cause of inherited cerebellar ataxia, accounting for 0.2% (1/585) of patients with dominantly inherited cerebellar ataxias in Taiwan. This study broadens the mutational spectrum of ITPR1 and also emphasizes the importance of considering ITPR1 mutations as a potential cause of inherited cerebellar ataxias.

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.

CANPMR Syndrome and Chromosome 1p32-p31 Deletion Syndrome Coexist in Two Related Individuals Affected by Simultaneous Haplo-insufficiency of CAMTA1 and NIFA Genes

Non-progressive cerebellar ataxia with mental retardation (CANPMR, OMIM 614756) and chromosome 1p32-p31 deletion syndrome (OMIM 613735) are two very rare inherited disorders, which are caused by mono-allelic deficiency (haplo-insufficiency) of calmodulin-binding transcription activator 1 (CAMTA1) and, respectively, nuclear factor 1 A (NFIA) genes. The yet reported patients affected by mono-allelic CAMTA1 dysfunction presented with neonatal hypotonia, delayed and ataxic gait, cerebellar atrophy, psychological delay and speech impairment, while individuals carrying a disrupted NFIA allele suffered from agenesis/hypoplasia of the corpus callosum, ventriculomegaly, developmental delay and urinary tract abnormalities. Both disorders were not seen in one patient together before. In this study two related individuals affected by a complex clinical syndrome, characterized by cognitive, neurological and nephrological features were studied for the underlying genetic disorder(s) by molecular cytogenetics. The two individuals present dysmorphic facies, macrocephaly, generalized ataxia, mild tremor, strabismus, mild mental retardation and kidney hypoplasia. Moreover, neuro-radiological studies showed hypoplasia of corpus callosum. Genetic investigations revealed a paracentric inversion in the short arm of one chromosome 1 with breakpoints within CAMTA1 and NFIA coding sequences. To the best of our knowledge, this is the first report of two patients harboring the simultaneous mono-allelic disruptions and consequent haplo-insufficiencies of two genes due to an inversion event. Disruption of CAMTA1 and NFIA genes led to neuro-psychological and nephrological dysfunctions, which comprised clinical features of CANPMR syndrome as well as chromosome 1p32-p31 deletion syndrome.

Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS. Here we report the detailed clinical, neuroimaging and genetic characterization of 18 PBS patients from 15 unrelated families. Biallelic LAMA1 variants were identified in 14 families (93%). The only non-mutated proband presented atypical clinical and neuroimaging features, challenging the diagnosis of PBS. Sixteen distinct variants were identified, which were all novel. In particular, the frameshift variant c.[2935delA] recurred in six unrelated families on a shared haplotype, suggesting a founder effect. No LAMA1 variants could be detected in 27 probands with different cerebellar dysplasias or non-progressive cerebellar ataxia, confirming the strong correlate between LAMA1 variants and PBS.

Previously Unreported Biallelic Mutation in DNAJC19: Are Sensorineural Hearing Loss and Basal Ganglia Lesions Additional Features of Dilated Cardiomyopathy and Ataxia (DCMA) Syndrome?

Dilated cardiomyopathy (DCM), non-progressive cerebellar ataxia (A), testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria are the hallmarks of DNAJC19 defect (or DCMA syndrome) due to biallelic mutations in DNAJC19. To date DCMA syndrome has been reported in 19 patients from Canada and in two Finnish siblings. The underlying pathomechanism is unknown; however, DNAJC19 is presumed to be involved in mitochondrial membrane related processes (e.g., protein import and cardiolipin remodeling). Here, we report an additional patient with progressive cerebellar atrophy and white matter changes. A Turkish boy presented at age 2 months with dilated cardiomyopathy (initially worsening then stabilizing in the second year of life), growth failure, bilateral cryptorchidism, and facial dysmorphism. Mental and motor developmental were, respectively, moderately and severely delayed. Profound intentional tremor and dyskinesia, spasticity (particularly at the lower extremities), and dystonia were observed. Sensorineural hearing loss was also diagnosed. MRI showed bilateral basal ganglia signal alterations. Plasma lactate levels were increased, as was urinary excretion of 3-methylglutaconic acid. He deceased aged 3 years. Sanger Sequencing of DNAJC19 confirmed the clinical diagnosis of DNAJC19 defect by revealing the previously unreported homozygous stop mutation c.63delC (p.Tyr21*). Investigation of enzymes of mitochondrial energy metabolism revealed decreased activity of cytochrome c oxidase in muscle tissue. Sensorineural hearing loss and bilateral basal ganglia lesions are common symptoms of mitochondrial disorders. This is the first report of an association with DNAJC19 defect.