Non-progressive Ataxia Research Articles

Structural and connectivity parameters reveal spared connectivity in young patients with non-progressive compared to slow-progressive cerebellar ataxia.

Within Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of compensatory strategies of the intact areas in NonP brain network. Eleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate whether eventual spared connectivity between basal ganglia and cerebellum explains the different postural motor behavior of NonP and SlowP patients. Cerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. This work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the possible compensatory role of basal ganglia in patients with stable cerebellar malformation.

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.

BRAT1 Mutation Retrospective Diagnosis: A Case Report

Biallelic mutations in the BRAT1 gene have been reported in cases with Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL), since 2012. Clinical features include progressive encephalopathy, dysmorphic features, microcephaly, hypertonia, developmental delay, refractory epilepsy, episodic apnea, and bradycardia. More recently, biallelic BRAT1 mutations have been associated with a milder phenotype in patients with migrating focal seizures in the absence of rigidity or with nonprogressive congenital ataxia with or without epilepsy (NEDCAS). It has been proposed that the loss of function caused by BRAT1 mutations may decrease cell proliferation and migration and cause neuronal atrophy through impairment of mitochondrial homeostasis. We here report a female infant with a phenotype, electroencephalogram (EEG), and brain magnetic resonance imaging (MRI) consistent with RMFSL, whose diagnosis was indirectly formulated three years after death upon the identification in both parents of a known pathogenetic variant in the BRAT1 gene. Our report emphasizes the remarkable potential of novel genetic technologies for the diagnosis of past unsolved clinical cases.

Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3-Related Syndrome.

Heterozygous mutations or deletions of the EBF3 gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of EBF3-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking. We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the EBF3 gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereas EBF3 variants were detected by whole exome sequencing. Phenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable. EBF3-related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose that EBF3-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.

Patient-Friendly Summary of the ACR Appropriateness Criteria®: Ataxia-Child

Not being able to move in a coordinated fashion is referred to as ataxia. Signs of ataxia include clumsiness, unsteady gait, nystagmus, and dysdiadochokinesis (inability to perform rapid alternating movements like foot tapping). Ataxia may be genetic or acquired, such as from illness or trauma. Acute onset ataxia develops within hours or days. In children with acute ataxia and no recent history of trauma, MRI head without and with contrast, MRI head without contrast, or CT head without contrast are usually appropriate. MRA head and/or neck, MRI spine, and CTA head and/or neck may be appropriate. For acute ataxia (following traumatic head or neck injury), MRI head without contrast or CT head without contrast are usually appropriate. MRA head and/or neck and CTA head and/or neck may be appropriate. For recurrent ataxia (episodes of ataxia followed by relatively symptom-free periods), MRI head without contrast is usually appropriate. MRI spectroscopy head or MRI head without and with contrast may be appropriate. For chronic progressive ataxia (symptoms typically appear and increase in severity over at least two months), MRI head without and with contrast or MRI head without contrast are usually appropriate. MRI complete spine without or with/without contrast, and CT head without contrast may be appropriate. For chronic nonprogressive ataxia (symptoms typically appear in first year of life, last more than two months, and do not change in severity), MRI head without contrast is usually appropriate. MRI complete spine without contrast and CT head without contrast may be appropriate.

Ataxia in children in the practice of a paramedic

The term ataxia includes impaired coordination and balance, and a lack of muscle control over intended movements. The most common signs and symptoms of cerebellar ataxia are ataxic gait (shaky, broad-based), movement disorders resulting from lack of proper muscular coordination, dysmetria, movement decomposition, intention tremor, and dysdiadachokinesia (disorder of alternating movements). Clinical symptoms vary depending on the damaged element: cerebellar hemisphere, cerebellar vermis, damage to the deep sensory pathways or damage to the cerebellar-frontal tracts and frontal centers. The most common causes of acute ataxia in children are drug overdoses, poisoning, and post-infectious cerebellitis. It is worth remembering that many causes of ataxia are metabolic and immunological. There are acute ataxias, intermittent and recurrent ataxias, chronic progressive and non-progressive ataxias. It should be remembered that each child with acute ataxia requires diagnosis and hospitalization. It is necessary to conduct a detailed interview regarding the time and circumstances of the onset of ataxia, accompanying symptoms, continuously and temporarily taken medications, possible previous episodes of these the symptoms themselves and the current state of health.

Study protocol of a randomised controlled trial for the effectiveness of a functional partial body weight support treadmill training (FPBWSTT) on motor and functional skills of children with ataxia

IntroductionA great heterogeneity characterises the paediatric population with ataxia, which has been studied poorly. The lack of postural control and coordination, in addition with features of the ‘ataxic’ gait are...

Clinical variability at the mild end of BRAT1-related spectrum: Evidence from two families with genotype-phenotype discordance.

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at theBRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder.

Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of KV4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. KV4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.

Focus on progressive myoclonic epilepsy in Berardinelli-Seip syndrome

Berardinelli-Seip syndrome or congenital generalized lipodystrophy type 2 is a rare genetic disorder characterized by selective loss of subcutaneous adipose tissue associated with peripheral insulin resistance and its complications. Nonprogressive mental retardation, dystonia, ataxia, and pyramidal signs are commonly present, whereas epilepsy has only occasionally been observed. We report the case of two sisters, 11 and 18 years old respectively, with an overlapping clinical phenotype compatible with Berardinelli-Seip syndrome and progressive myoclonic epilepsy. Molecular analysis identified an autosomal recessive c.1048C > t;(p(Arg350*)) pathogenic mutation of exon 8 of the BSCL2 gene, which was present in a homozygous state in both patients. Our paper contributes to further delineate a complex phenotype associated with BSCL2 mutation, underlining how seipin has a central and partially still unknown role that goes beyond adipose tissue metabolism, with a prominent involvement in central nervous system pathology.

Motor Function Improvement in Children with Ataxia Receiving Interval Rehabilitation, Including Vibration-Assisted Hometraining: A Retrospective Study.

Physiotherapy, including vibration-assisted therapy, has been proven to be effective for patients with ataxic cerebral palsy. Herewith, we studied the effect of a functional, goal-oriented interval rehabilitation program, including vibration-assisted home-training on the motor function of children with congenital ataxias. 45 children (mean age 7.7 years, SD 4.70) with ataxia, having received a 6-month home-based side-alternating vibration-assisted therapy combined with intensive, goal-oriented, functional rehabilitation intervals, were included in the study, classified according to the progressive or non-progressive ataxia character. Retrospective analysis of the prospectively collected data of the registry of the Cologne rehabilitation program "Auf die Beine". Motor abilities have been assessed prior to the intervention (M0), after 6 months of home-training (M6) as well as in a follow-up 6 months later (M12). We performed a gait analysis, a 1-minute walking test (1-MWT), and the Gross Motor Function Measure (GMFM-66). The GMFM-66 improvement (M6-M0 vs. M12-M6) was statistically significant with median improvement of 2.4 points (non-progressive) and 2.9 points (progressive) respectively, and clinically relevant. The 1-MWT improvement was statistically significant and clinically relevant for non-progressive ataxia. The intensive training, including vibration-assisted therapy significantly improved the motor function of children with ataxia. Six months later the skills were preserved in children with progressive ataxia and could be further developed in non-progressive forms.

VLDLR-associated Pontocerebellar Hypoplasia with Nonprogressive Congenital Ataxia and a Diagnostic Neuroimaging Pattern

VLDLR-associated Pontocerebellar Hypoplasia with Nonprogressive Congenital Ataxia and a Diagnostic Neuroimaging Pattern

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

Correction to: Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

The original version of this article unfortunately contained mistake in Fig.3 image.

A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome.

Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3'-terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c.278_279 + 2delACGT located at the 5'-end of ITPR1. The affected siblings were homozygotes, their parents heterozygous carriers and the variant was absent in the healthy son, indicating a recessive inheritance pattern. The deletion abolished the splice-donor site at exon 5/intron 5 junction, causing the skipping of exon 5 and the generation of a premature STOP codon. The mutation is predicted to result in the synthesis of a 64-amino acids nonfunctional protein. The mutant transcript comprised >96% of ITPR1 mRNA in the affected siblings, indicating that a small amount of wild-type transcript was still present. The novel autosomal recessive mutation here reported is the first variant affecting the ITPR1 N-terminal suppressor domain, thus extending the spectrum of the pathogenetic variants in GLSP and the range of the associated clinical manifestations.

Chapter 6 - Nonprogressive congenital ataxias

The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly. Neuroimaging is variable, ranging from normal cerebellar anatomy to reduced cerebellar volume (hypoplasia in the proper sense), and enlarged interfolial spaces, potentially mimicking atrophy. The latter appearance is often called "hypoplasia" as well, in view of the static clinical course. Some patients had progressive enlargement of cerebellar fissures, but a nonprogressive course. There is no imaging-clinical-genetic correlation. Dominant, recessive, and X-linked inheritance is documented for NPCA. Here, we focus on the still rather short list of dominant and recessive genes associated with NPCA, identified in the last few years. With future advances in genetics, we expect a rapid expansion of knowledge in this field.

A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect

The neuron-restricted isoform 3 of the plasma membrane Ca2+ ATPase plays a major role in the regulation of Ca2+ homeostasis in the brain, where the precise control of Ca2+ signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca2+ handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca2+-linked pathologies.

WES in nonprogressive congenital ataxia: Diagnostic yield and identification of novel loci

Objective: To explore the usefulness of whole-exome sequencing (WES) in the etiologic study of 14 unrelated patients with congenital ataxia (CA). Methods: All patients presented within the first year of life with hypotonia and developmental delay, followed by overt ataxic signs thereafter; intellectual disability was present in 10/14. Family history was negative but there were two consanguineous couples. All cases lacked any features allowing direct genetic testing, such as characteristic hindbrain abnormalities or metabolic biomarkers. MRI performed at the outset (age range 6–24 months) was normal (n = 6) or showed mild cerebellar atrophy (n = 8), in one case with hypomyelination. WES capture was performed in all 14 trios using Nimblegene SeqCap EZ Human Exome version 3, followed by sequencing on a HiSeq 2500 using 2×100bp read-length. Prioritization of causal variants was performed with the eDiVA software (http://www.ediva.crg.es/), which performs read alignment using bwa-mem, multi-sample variant prediction using GATK and variant prioritization using a random forest model trained on ClinVar and an in-house disease variant knowledge database. Results: We identified 14 variants in 10 trios. Twelve were Sanger-validated; five of these led to genetic diagnosis, comprising heterozygous de novo variants in CACNA1A, ITPR1 and STXBP1 and compound heterozygous variants in PIEZO2, and GJC2. In retrospect, pupillary abnormalities, arthrogryposis, seizures and hypomyelination could have represented useful hints to diagnosis in four cases. We additionally found homozygous variants in the new candidate gene DNAH14, encoding an axonemal dynein heavy chain, and heterozygous variants in SLC39A8, encoding a divalent cation transporter, previously associated with intellectual disability and cerebellar atrophy. Conclusions: In our CA cohort, WES allowed for diagnosis of 5/14 cases and identified a putative novel locus plus a new phenotype related to a known gene. We suggest that WES should be considered early in the diagnostic algorithm of CA with negative or unspecific imaging findings.

SCA13 causes dominantly inherited non-progressive myoclonus ataxia

IntroductionSpinocerebellar ataxia 13 (SCA13) is a rare autosomal dominant cerebellar ataxia. To our knowledge, its association to movement disorders has never been described. We aimed at reporting 8 new SCA13 cases with a focus on movement disorders especially myoclonus. MethodsWe performed a detailed neurological examination and neurophysiological recording in 8 patients consecutively diagnosed with SCA13 between December 2013 and October 2015 and followed up in two French tertiary centers. ResultsWe identified mild subcortical myoclonus in all patients, with a homogenous clinical and electrophysiological pattern. Myoclonus ataxia was very slowly progressive, like the other symptoms of the disease, whatever the age of onset. Patients with R423H mutation had an earlier age of onset than patients with R420H mutation. ConclusionsMyoclonus appears to be frequent in SCA13. SCA13 should be considered facing non-progressive autosomal dominant myoclonus ataxia, and polymyographic recording should be included in the diagnosis work.