Background
Huntington disease (HD) is a devastating neurodegenerative autosomal dominant genetic condition. Predictive testing (PT) is available through a defined protocol for at‐risk individuals. We ...analyzed the over‐24‐years evolution of practices regarding PT for HD in a single center.
Methods
We gathered data from the files of all individuals seeking PT for HD in Lyon, France, from 1994 to 2017.
Results
448 out of 567 participants had exploitable data. Age at consultation dichotomized over 24 years toward an eightfold increase in individuals aged >55 (2/94 vs. 30/183; 2% to 16%; p < .0001) and twice as many individuals aged 18–20 (3/94 vs. 12/183; 3%–7%; p < .05). Motives for testing remained stable. The rate of withdrawal doubled over 24 years (9/94 vs. 38/183; 9%–21%; p < .02). Independently of the time period, less withdrawal was observed for married, accompanied, at 50% risk, and symptomatic individuals, and in those able to explicit the motives for testing or taking the test to inform their children. We also assessed the consistency between the presence of subtle symptoms compatible with HD found before the test by the team's neurologist, and the positivity of the molecular test. The concordance was 100% (17/17) for associated motor and cognitive signs, 87% (27/31) for isolated motor signs, and 70% (7/10) for isolated cognitive signs. Furthermore, 91% (20/22) of individuals who requested testing because they thought they had symptoms, were indeed found carriers.
Conclusion
This over‐24 years study underlines an increasing withdrawal from protocol and a dichotomization of participants’ age. We also show a strong concordance between symptoms perceived by the neurologist or by the patient, and the subsequent positivity of the predictive molecular test.
The profile of the participants to presymptomatic testing for Huntington Disease has evolved over 24 years, with more older and younger individuals, and more withdrawal from the testing protocol. The presence of symptomatic patients has to be aknowledged among those participants for presymptomatic testing.
Biallelic WARS2 pathogenic variants responsible for partial defect in aminoacylation, have recently been reported in subjects presenting with late-onset phenotypes combining dopa-responsive ...early-onset dystonia parkinsonism with altered DaTSCAN and progressive myoclonus ataxia. Here, we present the case of a 39-year-old male with childhood-onset progressive dopa-responsive dystonia parkinsonism, prominent psychiatric features and ataxia whose genome sequencing identified a p.(Arg36Ter) nonsense variant and a hypomorphic p.(Trp13Gly) missense variant, allowing the diagnosis of WARS2-related disease. The p.(Trp13Gly) missense variant has previously been reported in individuals with less severe phenotypes than those carrying biallelic WARS2 loss-of-function variants. Among these individuals, two subjects had similar genetic backgrounds and almost identical clinical history to our patient. Our report brings additional proof that the p.(Trp13Gly) variant acts as a hypomorphic allele, offering insight on a genotype-phenotype correlation in WARS2-related disorders.Biallelic WARS2 pathogenic variants responsible for partial defect in aminoacylation, have recently been reported in subjects presenting with late-onset phenotypes combining dopa-responsive early-onset dystonia parkinsonism with altered DaTSCAN and progressive myoclonus ataxia. Here, we present the case of a 39-year-old male with childhood-onset progressive dopa-responsive dystonia parkinsonism, prominent psychiatric features and ataxia whose genome sequencing identified a p.(Arg36Ter) nonsense variant and a hypomorphic p.(Trp13Gly) missense variant, allowing the diagnosis of WARS2-related disease. The p.(Trp13Gly) missense variant has previously been reported in individuals with less severe phenotypes than those carrying biallelic WARS2 loss-of-function variants. Among these individuals, two subjects had similar genetic backgrounds and almost identical clinical history to our patient. Our report brings additional proof that the p.(Trp13Gly) variant acts as a hypomorphic allele, offering insight on a genotype-phenotype correlation in WARS2-related disorders.
Anorectal malformations (ARMs) represent a wide spectrum of congenital anomalies of the anus and rectum, of which more than half are syndromic. Their etiology is highly heterogeneous and still poorly ...understood. We report a 4-year-old girl who initially presented with an isolated ARM, and subsequently developed a global developmental delay as part of an ARID1B-related Coffin-Siris syndrome (CSS). A co-occurrence of ARMs and CSS in an individual by chance is unexpected since both diseases are very rare. A review of the literature enabled us to identify 10 other individuals with both CSS and ARMs. Among the ten individuals reported in this study, 8 had a variant in ARID1A, 2 in ARID1B, and 1 in SMARCA4. This more frequent than expected association between CSS and ARM indicates that some ARMs are most likely part of the CSS spectrum, especially for ARID1A-related CSS.
Background and ObjectivesNeurodevelopmental disorder with spastic diplegia and visual defect (NEDSDV) is a recently described rare syndrome caused by loss-of-function variations in CTNNB1 gene which ...includes developmental delay, intellectual deficiency, visual defects, and other features. Startle disease is not present in the classic clinical description and has been reported in only 2 patients so far. MethodsWe report 12 cases of patients with NEDSDV who present an exaggerated startle response including 1 patient observed in our department and 11 patients recruited by addressing a questionnaire to the members of the Facebook group of families of patients with a CTNNB1 pathogenic variant. We performed an EMG analysis of this abnormal startle response in 1 patient and a genotype-phenotype analysis of startle response in NEDSDV. ResultsAll 12 patients presented exaggerated startle responses to an unexpected stimulus. They provoked falls in 8 patients, causing injuries in 3, and 3 patients were afraid to walk. This startle disorder corresponds to atypic hyperekplexia. No genotype to phenotype correlation has been found to differentiate NEDSDV with or without startle disease. DiscussionOur data allow us to refine the phenotypic spectrum of patients affected by CTNNB1-related NEDSDV, suggesting that exaggerated startle reactions may be part of clinical features. A precise questioning on startle disorders should be performed systematically in these patients because they can lead to potentially traumatic falls, while effective treatments are available and can improve quality of life. CTNNB1 study should be considered in patients with startle disease associated with intellectual deficiency.
Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to ...molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered –1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
Pathogenic
variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure ...evolution, the presence of movement disorders, and the level of functional (in)dependence.
In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic
variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible.
Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living.
STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.
2 Image d’une patiente de 17 ans atteinte du syndrome cardio-facio-cutané (CFC) (Figure 1), qui présente une polyarthrite symétrique affectant les mains (articulations interphalangiennes sans ...atteinte des métacarpophalangiennes), les poignets, les coudes, les genoux et les chevilles, sans réveils nocturnes ou raideur matinale associés à une inflammation biologique. Aucune anomalie immunologique ni érosion (sur la radiographie ou en échographie) observées. La rémission clinique et biologique a été obtenue après trois mois de traitement par méthotrexate à la dose de 10 mg/semaine par voie sous-cutanée. Le syndrome CFC est une maladie génétique rare liée à des mutations activatrices des gènes de la voie RAS-MAPK (RAS/mitogen-activated protein kinase) 1. Dans notre cas, le CFC a été confirmé par la présence d’un variant hétérozygote c.275T>G dans le gène MAP2K1.
5‐Amino‐4‐imidazolecarboxamide‐ribosiduria (AICA)‐ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH ...(ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA‐riboside in urine. AICA‐ribosiduria had been reported in only one individual, 15 years ago. In this article, we report three novel cases of AICA‐ribosiduria from two independent families, with two novel pathogenic variants in ATIC. We also provide a clinical update on the first patient. Based on the phenotypic features shared by these four patients, we define AICA‐ribosiduria as the syndromic association of severe‐to‐profound global neurodevelopmental impairment, severe visual impairment due to chorioretinal atrophy, ante‐postnatal growth impairment, and severe scoliosis. Dysmorphic features were observed in all four cases, especially neonatal/infancy coarse facies with upturned nose. Early‐onset epilepsy is frequent and can be pharmacoresistant. Less frequently observed features are aortic coarctation, chronic hepatic cytolysis, minor genital malformations, and nephrocalcinosis. Alteration of the transformylase activity of ATIC might result in a more severe impairment than the alteration of the cyclohydrolase activity. Data from literature points toward a cytotoxic mechanism of the accumulated AICA‐riboside.
PDF
