Two cases with mitochondrial membrane protein-associated neurodegeneration: genetic features and long-term clinical follow-up.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological disease with childhood or adult onset. It is a subtype of clinically and genetically heterogeneous group of disorders, collectively known as neurodegeneration with brain iron accumulation . MPAN is generally associated with biallelic pathogenic variants in C19orf12. Herein, we describe genetic and clinical findings of two MPAN cases from Turkey. In the first case, we have identified the relatively common pathogenic variant of C19orf12 in the homozygous state, which causes late-onset MPAN. The second case was homozygous for an essential splice-site variation.

A Case of Leukoencephalopathy and Small Vessels Disease Caused by a Novel HTRA1 Homozygous Mutation.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a heritable, rare small vessel disease, which is caused by HTRA1 mutations and mostly reported Japanese and Chinese population. CARASIL is an orphan disease, which presents with progressive motor and cognitive impairment, alopecia, and spondylosis. The disease typically starts with lumbago at early twenties. Ischemic strokes start at mid-twenties. Patients have no cardiovascular or any other risk factors. Multiple lacunar infarcts and leukoencephalopathy cause progressive neurologic involvement. Leukoencephalopathy and small vessel disease without any risk factors is a significant finding for the differential diagnosis of HTRA1 gene pathology. This report presents clinical and genetic features of a rare case of typical CARASIL from Turkey who was followed with uncertain diagnoses for years.

Clinical and genetic spectrum of an orphan disease MPAN: a series with new variants and a novel phenotype.

INTRODUCTION: Pathogenic variations in C19orf12 are responsible for two allelic diseases: mitochondrial membrane protein-associated neurodegeneration (MPAN); and spastic paraplegia type 43 (SPG43). MPAN is an orphan disease, which presents with spasticity, dystonia, peripheral nerve involvement, and dementia. The pattern of iron accumulation on brain MRI may be a clue for the diagnosis of MPAN. SPG43, on the other hand, is characterised by progressive lower limb spasticity without brain iron accumulation. We here present clinical and genetic findings of MPAN patients with potentially pathogenic C19orf12 variants. MATERIALS AND METHODS: Patients from 13 different families having progressive motor symptoms with irritative pyramidal signs and brain iron accumulation were screened for C19orf12 gene variants. RESULTS: C19orf12 screening identified seven variants associated with MPAN in eight patients from seven families. We associated two pathogenic variants (c.24G > C; p.(Lys8Asn) and c.194G > A; p.(Gly65Glu)) with the MPAN phenotype for the first time. We also provided a genetic diagnosis for a patient with an atypical MPAN presentation. The variant c.32C > T; p.(Thr11Met), common to Turkish adult-onset MPAN patients, was also detected in two unrelated late-onset MPAN patients. CONCLUSIONS: Genetic analysis along with thorough clinical analysis supported by radiological findings will aid the differential diagnosis of MPAN within the neurodegeneration with brain iron accumulation spectrum as well as other disorders including hereditary spastic paraplegia. Dystonia and parkinsonism may not be the leading clinical findings in MPAN patients, as these are absent in the atypical case. Finally, we emphasise that the existence of frameshifting variants may bias the age of onset toward childhood.

Life-threatening parkinsonism-hyperpyrexia syndrome following bilateral deep brain stimulation of the subthalamic nucleus.

Parkinsonism-hyperpyrexia syndrome (PHS), or neuroleptic malignant syndrome (NMS), is a neurophysiologic reaction to the acute withdrawal/decrease of central dopamine levels. It is a severe complication characterized by rigidity, change in consciousness level, fever, hypertension, and autonomic instability, that can be fatal. To the best of our knowledge, PHS following deep brain stimulation (DBS) of subthalamic nucleus (STN) surgery due to anti-Parkinson drug discontinuation has been previously reported only six times. Half of these cases resulted in fatalities. Herein, we report on an early diagnosed case of PHS following bilateral STN-DBS which was successfully treated with the administration of dopamine agonists, fluid replacement, and activation of DBS.

A case with CMTX1 disease showing transient ischemic-attack-like episodes.

Charcot-Marie-Tooth (CMT) disease is a hereditary neurologic disease which affects the sensorial and motor fibers of the peripheral nerves. CMTX1 is an X-linked dominantly inherited subtype of CMT and is caused by mutations in gap junction beta 1 gene (GJB1). A small proportion of GJB1 mutations are associated with recurrent central nervous system findings. We describe a 15-year-old male patient with CMTX1 who had stroke-like findings along with foot deformities and peripheral neuropathy. Strokes and stroke-like attacks are rarely seen in children and adolescents. Herein, neurological signs, MRI findings and genetic results of a CMTX1 case are presented and discussed.

Combined thalamic and pallidal deep brain stimulation in diabetic hemiballism/hemichorea.

Hemiballism/hemichorea (HH) is a hyperkinetic movement disorder observed mostly in older adults with cerebrovascular diseases. Although the symptoms improve without any treatment, lesioning or DBS (deep brain stimulation) may be rarely required to provide symptomatic relief for patients with severe involuntary movements. HH is a rare complication of uncontrolled diabetes. There are only a few reported cases of diabetic HH that have been surgically treated. Thus, herein, we have reported the case of a 75-year-old female with type-II diabetes mellitus that presented with disabling involuntary limb movements of the left side, despite being treated conservatively for six months. DBS targeting the globus pallidus internus (GPi) and ventral intermediate (Vim) thalamic nucleus was performed. Complete resolution of symptoms was achieved with a combined stimulation of the thalamic Vim nucleus (at 1.7 mA) and GPi (at 2.4 mA). The combined stimulation of the Vim nucleus and GPi effectively resolved the diabetes-induced HH symptoms in our patient. Thus, although certain conclusions cannot be drawn due to the rarity of the surgically treated patients with HH, the combined stimulation is a novel treatment option for resistant HH.

Clinical and genetic analyses in syndromic intellectual disability with primary microcephaly reveal biallelic and de novo variants in patients with parental consanguinity.

BACKGROUND: Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES). OBJECTIVE: This study was performed to dissect the clinical and genetic features in five distinct IDM cases. METHODS: Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed. RESULTS: We have identified biallelic loss of function variants in genes WDR62 and AP4M1 in three families, together with de novo missense variants in genes SOX11 and TRIO in two families. ES based haplotype analysis in two cases upon identification of an identical WDR62 variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in TRIO via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant. CONCLUSION: In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.

Early developmental support for preterm infants based on exploratory behaviors: A parallel randomized controlled study.

INTRODUCTION: Preterm infants are at high risk for developmental disabilities, and their parents are at increased risk for high stress. Early intervention programs are applied to reduce these adverse outcomes. The primary aim is to compare the efficacy of the novel Explorer Baby early intervention program for the holistic development of preterm infants. The second objective was to compare the stress levels of their mothers. METHODS: Randomized clinical trial with 38 weeks-6 months corrected age preterm infants at low risk for cerebral palsy, randomly assigned to experimental (Explorer Baby) or active control neurodevelopmental therapy (NDT) groups. Fifty-seven infants were enrolled in the study, and 51 (26 Explorer Baby, 25 NDT) completed it. Bayley III was used as a primary outcome before, during, and after the intervention. RESULTS: When we compared the changes between the groups before and after therapy, no significant differences were found in any of the primary or secondary outcomes (between-group comparisons). When comparing the changes in both groups before and after therapy (in-group comparison), the Explorer Baby group demonstrated significant improvements in cognitive (Hedges' g = .83) and explorative language skills (Hedges' g = .65), whereas the NDT group showed improved parent-child dysfunctional interaction (Hedges' g = 2.66) between T0-T1 and T0-T2. CONCLUSIONS: The Explorer Baby early intervention program may be a preferred option to support premature infants without brain injury, as it shows greater skill acquisition than NDT, although not statistically significant. Both methods are safe as they support premature babies without negatively affecting mothers' overall stress levels.

Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.

INTRODUCTION: Next generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human. METHODS: We have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ELOVL1 protein structure was computationally modelled. RESULTS: The novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC-MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides. DISCUSSION: It has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy.

A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis.

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.

De novo 8p23.1 deletion in a patient with absence epilepsy.

The 8p23.1 deletion syndrome is a rare multisystem disorder with high penetrance and a variable phenotypic spectrum that includes congenital heart disease (CHD), intellectual disability, behavioural problems, microcephalia, and sometimes epilepsy. Genomic copy number variations (CNVs) constitute an important genetic risk factor for common genetic generalised epilepsy syndromes (GGEs) and absence seizures. These variations, resulting either from copy loss (microdeletion) or copy gain (duplications), disrupt genes associated with neuronal development. Herein, we report an epilepsy patient who was affected by developmental delay, microcephalia, behavioural problems, CHD, and childhood-onset absence seizures. The patient had a 4-Mb de novo microdeletion at 8p23.1. Some of the genes in this region, particularly XKR6 and MIR597, may be involved in the pathogenesis of absence seizures, suggesting that epilepsy may possibly be part of the phenotypic spectrum of the syndrome rather than a comorbid disorder. Thus, CNV screening for GGE plus patients may have important implications in clinical practice with regards to diagnostic classification, clinical management of the syndromic multisystem disorders, and, potentially, genetic counselling.

Clinical and genetic features of PKAN patients in a tertiary centre in Turkey.

OBJECTIVE: Pantothenate kinase-associated neurodegeneration (PKAN) is caused by mutations of the pantothenate kinase 2 (PANK2) gene. The major clinical sign of PKAN is dystonia and the eye-of-the-tiger pattern on the MRI has been a clue for the diagnosis. We aim to discuss clinical and genetic findings of 22 PKAN patients from 13 families. METHODS: Twenty-two patients were clinically diagnosed with PKAN and screened for PANK2 mutations. The patients were classified according to their onset age and progression rate. RESULTS: Mutation screening revealed 5 novel and 7 previously reported sequence variants in PANK2. The variants identified were in the form of missense changes, small exonic deletions and intronic mutations with a probable splicing effect. The presenting features were dystonia and gait disturbance in early onset patients, whereas the presenting symptoms were variable for the late onset group. The progression rate of the disease was not uniform. CONCLUSION: The current report is the first patient series of PKAN from Turkey that expands the clinical and genetic spectrum of the disease.

A novel gene mutation in PANK2 in a patient with severe jaw-opening dystonia.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurodegenerative condition. Major clinical features include progressive dystonia, pigmentary retinopathy, spasticity, and cognitive decline. The typical MRI sign of the disease, known as "eye-of-the-tiger", is what makes differential diagnosis possible. We here describe a 16-year-old male patient with PKAN presenting with severe and sustained jaw-opening dystonia which may be due to heterogeneous etiologies showing poor response to treatment. Herein, long-term follow-up and genetic results of a PKAN case who experienced severe jaw-opening dystonia are presented and discussed.