Psychomotor Regression Research Articles

Catatonia in children and adolescents: New perspectives

IntroductionCatatonia is a rare and severe psychomotor condition in children and adolescents. In the current report, we aimed to review the recent literature. MethodUsing a PRISMA approach, we searched MEDLINE between 1982 and 2017 using the keywords ‘CATATONIA’ and ‘CHILD’ or ‘ADOLESCENT’. In total, we reviewed 130 reports (controlled study, N=4; clinical chart, N=23; case report, N=54; and editorial/review, N=42). ResultsSeveral aspects seem to be age specific: (1) although the clinical presentation resembles that in adults, some symptoms are important in children and adolescents (e.g., psychomotor regression). (2) Associated disorders are similar to that found in adults; however, schizophrenia is more frequently observed than mood disorder. Additionally, a history of neurodevelopmental disorders maybe encountered. (3) Morbidity and mortality are among the worst in child psychiatry. (4) Underlying organic conditions are highly prevalent (>20% of the cases), and their search is warranted because some diagnoses may result in specific treatments (e.g., immune-suppressor therapy for autoimmune conditions). (5) Symptomatic approaches – high dose of benzodiazepines and electroconvulsive therapy (ECT) – are as efficient in children or adolescents as they are in adults, but this finding needs to be acknowledged because a resistance against the use of ECT or high-dose medication exists among child psychiatrists. DiscussionRecent advances in child and adolescent catatonia research have offered major improvements in understanding catatonia and in new therapeutic opportunities. The syndrome is rare, but these advances need to be acknowledged in order to direct patients to centers that have developed a specific expertise.

Severe cognitive impairment and early-onset epilepsy in six patients with the de novo p.Glu590Lys variant of CUX2

Objective: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching branching, spine development, and synapse formation in layer II-III neurons of the cerebral cortex. Abnormal dendrites and synapses in Cux2(−/−) mice correlate correlate with reduced synaptic function and defects in working memory. A de novo CUX2 p.Glu590Lys variant was reported in two patients involved in large-scale scale whole-exome sequencing (WES) studies on intellectual disability and epileptic epileptic encephalopathies. We report on clinical data of six patients carrying t the de novo p.Glu590Lys variant. Methods: We reviewed clinical, MRI and EEG data from 6 patients, including 2 previously reported reported and 4 additional cases. The p.Glu590Lys variant was identified by WES in 3 and through a targeted gene panel in three. It had occurred de novo in all of them. Results: There were 4 males and 2 females. Mean age at inclusion was 13.6 years [8–21]. Epilepsy occurred in all patients. Age at onset of seizures ranged from 2 months to 1 year [mean = 6.6 months]. Seizure types at onset were myoclonic seizures, atypical absence with myoclonic component, and focal seizures. Seizures were drug-resistant in all patients but one. EEG initially showed generalized polyspikes and waves (4) or multifocal epileptiform discharges (2). Two patients are seizure-free under treatment whereas the others still have persistent seizures. Cognitive regression was noticed in childhood at least for two patients, at 8 and 12 years, respectively. All patients had severe cognitive impairment and autistic features were present in 4. Two patients had ataxic gait. Brain MRI only showed minor and non-specific anomalies. Conclusions: This study shows that patients carrying the p.Glu590Lys variant of CUX2 display a relatively homogeneous clinical presentation with infantile-onset epilepsy epilepsy frequently including myoclonic jerks with polyspikes and waves or multifocal epileptiform discharges. Patients have severe cognitive impairment sometimes associated with psychomotor regression in childhood.

It’s a Boy: Ethical Implications of the First Spindle Nuclear Transfer Birth

It’s a Boy: Ethical Implications of the First Spindle Nuclear Transfer Birth

PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.

Here we present four unrelated families with six individuals that have infantile-onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families. Mutations in genes encoding aminoacyl-tRNA synthetases cause gene-specific mitochondrial disorders. Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement. Moreover, it is known that NARS2 mutations cause various clinical phenotypes, including non-syndromic hearing loss, Leigh syndrome, intellectual disability with epilepsy and severe myopathy. The individuals with PARS2 and NARS2 mutations, we have reported here demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. Our data broaden the clinical and mutational spectrum of PARS2- and NARS2-related disorders.

Novel Mutation in PLA2G6 Gene in a Patient with Infantile Neuroaxonal Dystrophy

AbstractInfantile neuroaxonal dystrophy (INAD) is an autosomal recessive disorder that causes psychomotor regression. Clinicopathological features include truncal hypotonia followed by spastic quadriparesis, strabismus, nystagmus, cerebellar ataxia, bulbar dysfunction, and cerebellar atrophy. INAD is associated with a variety of mutations in the PLA2G6 gene that encodes the group VI calcium-independent phospholipase A2 protein which is important in cell membrane homeostasis. Defects in this protein cause axonal dystrophy. We report a 2-year-old boy with INAD who was found to have a novel deletion c.1019_1025del7 leading to a frame shift in the PLA2G6 gene. We suggest that this change may be an addition to the array of mutations causing INAD.

Novel mutations in IBA57 are associated with leukodystrophy and variable clinical phenotypes.

Defects of the Fe/S cluster biosynthesis represent a subgroup of diseases affecting the mitochondrial energy metabolism. In the last years, mutations in four genes (NFU1, BOLA3, ISCA2 and IBA57) have been related to a new group of multiple mitochondrial dysfunction syndromes characterized by lactic acidosis, hyperglycinemia, multiple defects of the respiratory chain complexes, and impairment of four lipoic acid-dependent enzymes: α-ketoglutarate dehydrogenase complex, pyruvic dehydrogenase, branched-chain α-keto acid dehydrogenase complex and the H protein of the glycine cleavage system. Few patients have been reported with mutations in IBA57 and with variable clinical phenotype. Herein, we describe four unrelated patients carrying novel mutations in IBA57. All patients presented with combined or isolated defect of complex I and II. Clinical features varied widely, ranging from fatal infantile onset of the disease to acute and severe psychomotor regression after the first year of life. Brain MRI was characterized by cavitating leukodystrophy. The identified mutations were never reported previously and all had a dramatic effect on IBA57 stability. Our study contributes to expand the array of the genotypic variation of IBA57 and delineates the leukodystrophic pattern of IBA57 deficient patients.

Régression psychomotrice par carence en vitamine B12

The vitamin B12 reserves of newborns are dependent on transplacental transfer and secondarily on food intake. This vitamin is involved in hematopoiesis and in neurological development. We report the case of a severe vitamin B12 deficiency in a 7-month-old infant. A neurological evaluation performed at 5 months of age for psychomotor regression found nonspecific cortical atrophy. The infant was hospitalized for impaired general condition and worsening of neurological symptoms. Examinations revealed bicytopenia with normocytic anemia (Hb: 7.4g/dl, MCV: 84μm3). The combination of psychomotor regression, malnutrition, and anemia suggested there was a deficiency, specifically of vitamin B12 (blood values of <50pg/mL, normal range=200-1000); bone marrow aspiration showed characteristics of megaloblastic dystrophy. Psychomotor regression associated with hematological disorders and a failure to thrive can be related to vitamin B12 deficiency. Replacement therapy must be established as early as possible to avoid potentially irreversible neurological damage.

Observaţii şi reflecţii pe baza experienţei îngrijirii vârstnicului fragil

Studies dedicated to the process of frailty in geriatrics and gerontology, and also the attempts to individualize a new geriatric syndrome it was a concern in the last years. The authors of this paper, having an unique experience in caring for frail elderly (one of us directly cared frail elderly patients for more than thirty years) have accumulated many observation – clinical, laboratory, nursing and prevention – opportunity for reflection based on author’s opinions. The most important reflection expresses primarily the difficulty to mark off such a syndrome, to have a consensus, which is a condition to integrate a new entity. The rich semiology of elderly patients, the (multi) functional decline inspired over the years many researchers who elaborated nosological descriptions overlapped, more or less to the frailty syndrome. UNO proposed from several years a classification of elderly in the “active elderly” and “frail elderly”. Others described the psycho-motor regression has described as “elder’s multiple vulnerabilities syndrome”. Moreover, frailty is not a specific status of the elderly, but it could be interpreted rather as a “state” than a syndrome, such as bedridden condition, terminal condition, state of dependence, severe stages of dementias and so on. Despite the difficulties of defining the concept of frailty brings some benefit concerning the understanding of the specificity of elderly patient, the holistic approach of his problems, not least provides tools to indicate the need of preventive measures, with good effects on the longevity and the quality of life.

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome.

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.

Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome.

Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.

PP03.10 – 2967: Niemann-Pick C disease: Diagnostic challenge

Introduction Niemann-Pick C Disease (NPCD) is an autosomal recessive storage lipidosis due to a disorder of cholesterol esterification leading to the accumulation of sphingomyelin and cholesterol in the brain, liver and spleen. The heterogeneous clinical presentation of NPCD makes diagnosis difficult. We report a case of late-infantile NPCD in a child with prolonged neonatal jaundice followed by psychomotor regression at the age of 2 and white matter abnormalities. Clinical case We present a 4-year-old boy with progressive neurological regression. He was born by caesarean at term to a consanguineous family. Apgar was normal. During the neonatal period, a severe jaundice was treated by several exsanguinous transfusions. He presented a mild motor and language delay, but experienced a severe neurological regression at the age of 2. At presentation, the child had axial hypotonia, spastic quadriplegia, strabismus, failure to thrive with swallowing disorder and dysmorphic features. He subsequently developed seizures. Sequential brain MRI's showed progressive white matter involvement with a decrease in volume and signal hyperintensity on T2-weighted images, a thinning of corpus callosum and a large pituitary gland. Abdominal ultrasound detected a globular spleen without liver or spleen enlargement. Routine laboratory biochemistry profiles showed elevated aspartate aminotransferase (ASAT) activity. Nerve conduction velocities displayed a demyelinating polyneuropathy. Bone-marrow examination revealed the presence of foam cells, suggestive of NPCD. The culture of skin fibroblasts in lipid-deficient medium, using filipin stain, showed the presence of dark punctate granules, confirming the diagnosis of NPCD. Sequencing analysis showed a homozygous mutation c.1340A>G in NPC-1 gene. Conclusions This case illustrates a late-onset infantile form of Niemann-Pick C disease. We should consider NPCD as a diagnosis possibility in any patient with neonatal jaundice and psychomotor regression, especially if there is white matter involvement. Careful clinical history and bone marrow analysis were helpful to the diagnosis.

PP03.13 – 2568: Two further Greek cases of Krabbe disease and a new mutation in the GALC gene

Objective Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme galactocerebrosidase (GALC) and is classified into infantile and late-onset form, depending on the age of onset. Methods and results We report two Greek patients with Krabbe disease with the infantile and late-infantile forms, respectively. The first patient was admitted at the age of 3.5 months, due to generalized hypertonia and developmental delay. A brain MRI demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased. A severe reduction in â-galactocerebrosidase activity (0.003 nmol/mg protein/hr, normal range 0.1–0.97 units), indicated the diagnosis of Krabbe disease, which was confirmed by molecular genetic testing (an homozygous c.411_413delTAA [K139del] mutation in the GALC gene). The second patient manifested with psychomotor regression at the age of 6 months, while the brain MRI was normal. At the age of 18 months, a repeated brain MRI demonstrated leukodystrophic changes, whereas NCVs were significantly delayed, too. A total lack of â-galactoserebrosidase activity (0.00 nmol/mg protein/hr, normal range 0.1–0.97 units) led to further molecular genetic testing, which revealed a homozygous c.749T>C [p.I250T] mutation in the GALC gene. At their last follow-up visit at the age of 4 and 10 years, respectively, both patients were bed-ridden and demonstrated the clinical picture of spastic tetraplegia suffering from frequent infections of the respiratory tract and fed through a gastrostomy catheter. Conclusion The c.411_413delTAA [K139del] mutation is the first reported in the literature, while there are another two reports of patients bearing the c.749T>C [p.I250T] mutation. Interestingly, both these patients were of Greek ancestry, a fact that could be indicative of a founder effect. Genotyping of patients of Krabbe disease is important, in order to contribute to a European mutation database and to further study possible genotype-phenotype correlations.

P109 – 2442: Infantile neuroaxonal dystrophy: A new mutation

Objective Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disorder characterised by rapid cognitive and motor regression, axial hypotonia, gait disturbance, limb spasticity, cerebellar signs, and optic atrophy. Although magnetic resonance imaging (MRI) can sometimes contribute towards the diagnosis, the confirmation of INAD is by Pla2G6 gene analysis. Methods A patient is presented with motor retardation, hypotonia and diagnosed as INAD with a new mutation. Results We report a two years old boy who was referred with difficulty in walking and frequent falls. He has started walking and talking at the age of one. He couldn't make two words sentence. He has two siblings of whom one of them had similar findings. He Her early psychomotor development was normal till 1 year of age. From age 1, she stopped making progress and subsequently she developed seizures, mental regression and became bedridden. Her MRI revelaed cerebellar atrophy. She died at the age of six without diagnosis. His other sister was at the age of 16 and her medical history was unremarkable. The parents have a third-degree consanguinity. Neurological examination of our case showed hypotonia and had areflexia. His initial MRI was normal whereas the following MRI after nine months revealed cerebellar vermian hypoplasia. Metabolic screening tests were normal (Tandem mass spectroscopy, very long chain fatty acid, plasma and urine aminoacids, transferin isoelectric focusing for CDG). Electromyography showed motor axonal neuropathy. His visual examination was normal. Molecular analysis of PLA2G6 gene demonstrated a novel homozygous P.G586R (c.1756G>A) mutation. Conclusion Our case indicates that INAD should be kept in mind in the differential diagnosis of patients with hypotonia and psychomotor regression.

P191 – 2505: Two siblings with a CDKL5 mutation: Genotype and phenotype evaluation

Objective This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in two sisters. Their phenotype is different despite an identical genotype Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. However, CDKL5 patients experience a developmental delay from from birth onwards and seizures starts the first three months of life. Methods Advanced genetic evaluations of the sisters and parents, the electropherogram, clinical and electroencephalographic (EEG) features of both sisters are discussed. Results In the youngest patient, who was known to us prior to appearance of the clinical symptoms, neurological and EEG evaluations at the age of 6 weeks were normal. Infantile spasms evolved at the age of 10 weeks. Simultaneously, she showed a psychomotor regression and deterioration of the EEG into a severe epileptic pattern. Her older sister, was from the start severely hypotonic, had a developmental delay (without regression) and feeding problems and experiences seizures from the age of 8 weeks. In both seizures are refractory. The phenotype of the youngest sister is worse than that of her older sister, despite an identical genotype. This may be explained by differences in X-chromosomal inactivation and other unknown epigenetic and environmental factors. Unfortunately, X inactivation pattern could not be determined in the youngest sister. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Conclusion This report of familial recurrence with suspected germline mosaicism in a healthy parent, has important consequences for genetic counselling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased.

G59 The international collaborative infantile spasms study (iciss) comparing hormonal therapies (prednisolone or tetracosactide depot) and vigabatrin versus hormonal therapies alone in the treatment of infantile spasms: early clinical outcome

Infantile spasms (IS) are a serious epileptic encephalopathy that occur most commonly between 2 and 14 months. The spasms occur in association with hypsarrhythmia or similar on EEG. There is often coincident psychomotor arrest or regression. Between March 2007 and May 2014, infants with IS and a compatible EEG were enrolled in a multicenter treatment trial. Participating countries were the UK, Germany, Switzerland, Australia and New Zealand. Infants were randomised to receive either hormonal therapy and vigabatrin or hormonal therapy alone. A second stage randomization allowed hormonal treatment to be allocated as either prednisolone or tetracosactide depot. Minimum doses were: vigabatrin 100 mg/kg/day, prednisolone 40 mg per day, or IM tetracosactide depot 0.5 mg on alternate days. Hormonal treatment was continued for 2 weeks and then weaned over 2 weeks. Vigabatrin was continued for 3 months and then weaned over a month. The early primary outcome measure was cessation of spasms on and between days 14 and 42. Analysis is by intention to treat. 377 children were enrolled and early clinical outcome data will be available on 376 (1 case withdrew). 186 were allocated hormonal therapy and vigabatrin and 191 were allocated hormonal therapy alone. We will report on the primary clinical outcome and serious adverse clinical events. Developmental outcome at 18 months of age will be reported in a subsequent paper. To date this is by far the largest treatment study of infantile spasms ever undertaken.

Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.

BackgroundMultiple sulfatase deficiency is a rare inherited metabolic disorder caused by mutations in the SUMF1 gene. The disease remains poorly known, often leading to a late diagnosis. This study aimed to provide improved knowledge of the disease, through complete clinical, biochemical, and molecular descriptions of a cohort of unrelated patients. The main objective was to identify prognostic markers, both phenotypic and genotypic, to accelerate the diagnosis and improve patient care.MethodsThe phenotypes of ten unrelated patients were fully documented at the clinical and biochemical levels. The long-term follow-up of each patient allowed correlations of the phenotypes to the disease outcomes. Each patient’s molecular defects were also identified. Site-directed mutagenesis was used to individually express the mutants and assess their stability. Characterisation of the protein mutants was completed by in silico analyses based on sequence comparisons and structural models.ResultsThe most severe cases were characterised by the presence of non-neurological symptoms as well as the occurrence of psychomotor regression before 2 years of age. Nine novel SUMF1 mutations were identified. Clinically severe forms were often associated with SUMF1 mutations that strongly affected the protein stability and/or catalytic function as predicted from in silico and western blot analyses.ConclusionsThis detailed clinical description and follow-up of a cohort of patients, together with the molecular characterisation of their underlying defects, contribute to improved knowledge of multiple sulfatase deficiency. Predictors of a bad prognosis were the presence of several non-neurological symptoms and the onset of psychomotor regression before 2 years of age. No strict correlation existed between in vitro residual sulfatase activity and disease severity. Genotype–phenotype correlations related to previously reported mutants were strengthened. These and previous observations allow not only improved prediction of the disease outcome but also provision of appropriate care for patients, in the expectation of specific treatment development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0244-7) contains supplementary material, which is available to authorized users.

CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.

From ventriculomegaly to severe muscular atrophy: Expansion of the clinical spectrum related to mutations in AIFM1

The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5years he developed hearing loss and severe ataxia and at age 10years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.

Infantile and childhood onset PLA2G6-associated neurodegeneration in a large North African cohort.

Mutations in the PLA2G6 gene are causative of PLA2G6-associated neurodegeneration (PLAN), a spectrum of neurodegenerative conditions including infantile, childhood and adult onset forms. Seventeen North African patients with a clinical suspicion of infantile-onset PLAN underwent clinical, neurophysiological and neuroimaging examinations, and PLA2G6 sequencing. Haplotype analysis was performed to date the identified founder mutation. All patients carried biallelic mutations in PLA2G6. Sixteen children had the commonest form of infantile-onset PLAN, with early onset of psychomotor regression, hypotonia, pyramidal and cerebellar signs, and abnormal ocular movements. The phenotype was highly homogeneous, with rapid development of severe spastic tetraparesis, cognitive impairment and optic atrophy. Neuroimaging showed cerebellar atrophy and claval hypertrophy to be the commonest and earliest signs, whilst cerebellar cortex hyperintensity and pallidal iron deposition were later findings. Motor or sensory-motor neuropathy and electroencephalogram fast rhythms were also frequent. Nine patients from six families shared the same founder mutation (p.V691del) which probably arose by the late seventeenth century. Only one patient fitted the diagnosis of the much rarer childhood-onset PLAN. Despite the early onset (18 months), clinical progression was slower, with behavioral disturbances and dystonia. Typical features of infantile-onset PLAN such as hypotonia, nystagmus/strabismus, optic atrophy, electroencephalogram fast rhythms and motor neuropathy were absent. Cerebellar atrophy, claval hypertrophy and pallidal hypointensity were evident at brain magnetic resonance imaging. This patient carried a missense variant predicted to be less deleterious. The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs

BackgroundWe present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. Case presentationA 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. ResultsMECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. ConclusionNCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.