Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare congenital autosomal recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa ...decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human AADC gene into the putamina has become available. This systematic review on PubMed, Scopus databases, and other sources is aimed at describing the AADC whole phenotypic spectrum in order to facilitate its early diagnosis. Literature reviews, original articles, retrospective and comparative studies, large case series, case reports, and short communications were considered. A database was set up using Microsoft Excel to collect clinical, molecular, biochemical, and therapeutic data. By analysing 261 patients from 41 papers with molecular and/or biochemical diagnosis of AADC deficiency for which individuality could be determined with certainty, we found symptom onset to occur in the first 6 months of life in 93% of cases. Hypotonia and developmental delay are cardinal signs, reported as present in 73.9% and 72% of cases, respectively. Oculogyric crises were seen in 67% of patients while hypokinesia in 42% and ptosis in 26%. Dysautonomic features have been revealed in 53% and gastrointestinal symptoms in 19% of cases. With 37% and 30% of patients reported being affected by sleep and behavioural disorders, it seems to be commoner than previously acknowledged. Although reporting bias cannot be excluded, there is still a need for comprehensive clinical descriptions of symptoms at onset and during follow-up. In fact, our review suggests that most of the neurological and extraneurological symptoms and signs reported, although quite frequent in this condition, are not pathognomonic, and therefore, ADCC deficiency can remain an underdiscovered disorder.
Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early ...brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility.
We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia.
To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.
The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe ...disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children's Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.
Abstract
Background
Tolosa-Hunt syndrome (THS) and recurrent painful ophthalmoplegic neuropathy (RPON) are rare diseases reported within the “Painful lesions of the cranial nerves” section of the ...International Classification of Headache Disorders-3
rd
edition (ICHD-3). In case of a first painful attack, differential diagnosis could be challenging and many pitfalls are due to the rarity of the disorders and the lack of information about correct medical management in youngsters.
Case presentation
Our main purpose was to report a new case of THS and a new case of RPON describing management and diagnostic investigation at the time of the first episode.
In both cases of THS (13 years old) and RPON (14 years old) a unilateral periorbital headache associated with acute onset of ipsilateral third cranial nerve paresis, scarcely responding to non-steroidal anti-inflammatory drugs (NSAID), was present at the beginning of the first attack. Brain MRI with "time-of-flight" (TOF) angiography and the need to administer steroids (after 72 h from onset) in order to stop pain were the most important handles allowing us to adopt the correct management both in THS or RPON since onset and to face recurrences in RPON by avoiding useless therapy during follow-up.
Conclusion
Unilateral periorbital headache associated with third-fourth or sixth cranial nerve paresis should ideally be investigated with a full work-up, comprehensive of brain MRI with TOF angiography since the first attack. In cases with negative brain MRI spontaneous resolution should be considered and watchful waiting might be advisable before starting steroid therapy.
Mapping brain functions is crucial for neurosurgical planning in patients with drug-resistant seizures. However, presurgical language mapping using either functional or structural networks can be ...challenging, especially in children. In fact, most of the evidence on this topic derives from cross-sectional or retrospective studies in adults submitted to anterior temporal lobectomy. In this prospective study, we used fMRI and DTI to explore patterns of language representation, their predictors and impact on cognitive performances in 29 children and young adults (mean age at surgery: 14.6 ± 4.5 years) with focal lesional epilepsy. In 20 of them, we also assessed the influence of epilepsy surgery on language lateralization. All patients were consecutively enrolled at a single epilepsy surgery center between 2009 and 2015 and assessed with preoperative structural and functional 3T brain MRI during three language tasks: Word Generation (WG), Rhyme Generation (RG) and a comprehension task. We also acquired DTI data on arcuate fasciculus in 24 patients. We first assessed patterns of language representation (relationship of activations with the epileptogenic lesion and Laterality Index (LI)) and then hypothesized a causal model to test whether selected clinical variables would influence the patterns of language representation and the ensuing impact of the latter on cognitive performances. Twenty out of 29 patients also underwent postoperative language fMRI. We analyzed possible changes of fMRI and DTI LIs and their clinical predictors. Preoperatively, we found atypical language lateralization in four patients during WG task, in one patient during RG task and in seven patients during the comprehension task. Diffuse interictal EEG abnormalities predicted a more atypical language representation on fMRI (p = 0.012), which in turn correlated with lower attention (p = 0.036) and IQ/GDQ scores (p = 0.014). Postoperative language reorganization implied shifting towards atypical language representation. Abnormal postoperative EEG (p = 0.003) and surgical failures (p = 0.015) were associated with more atypical language lateralization, in turn correlating with worsened fluency. Neither preoperative asymmetry nor postoperative DTI LI changes in the arcuate fasciculus were observed. Focal lesional epilepsy associated with diffuse EEG abnormalities may favor atypical language lateralization and worse cognitive performances, which are potentially reversible after successful surgery.
Charcot-Marie-Tooth (CMT) is a group of inherited peripheral neuropathies characterized by wide genotypic and phenotypic variability. The onset is typically in childhood, and the most frequent ...clinical manifestations are predominantly distal muscle weakness, hypoesthesia, foot deformity (pes cavus) and areflexia. In the long term, complications such as muscle-tendon retractions, extremity deformities, muscle atrophy and pain may occur. Among CMT1, demyelinating and autosomal dominant forms, CMT1G is determined by mutations in the PMP2 myelin protein.
Starting from the index case, we performed a clinical, electrophysiological, neuroradiological and genetic evaluation of all family members for three generations; we identified p.Ile50del in PMP2 in all the nine affected members. They presented a typical clinical phenotype, with childhood-onset variable severity between generations and a chronic demyelinating sensory-motor polyneuropathy on the electrophysiologic examination; the progression was slow to very slow and predominant in the lower limbs. Our study reports a relatively large sample of patients, members of the same family, with CMT1G by PMP2, which is a rare form of demyelinating CMT, highlighting the genetic variability of the CMT family instead of the overlapping clinical phenotypes within demyelinating forms. To date, only supportive and preventive measures for the most severe complications are available; therefore, we believe that early diagnosis (clinical, electrophysiological and genetic) allows access to specialist follow-up and therapies, thereby improving the quality of life of patients.
Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and ...complicated forms.
We report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene.
We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.
We aimed to report on previously unappreciated clinical features associated with
-related intellectual disability (ID) syndrome, a rare neurodevelopmental disorder characterized by global ...developmental delay, intellectual disability, and language delay, with or without autistic features.
We performed whole-exome sequencing (WES) to molecularly characterize an individual presenting with ID, epilepsy, autism spectrum disorder, behavioral problems, and facial dysmorphisms as major features.
WES allowed us to identify a previously unreported
splice site variant, c.1429-1G>T (NM_032682.6), in the
gene (OMIM
605515) as the causative event underlying the phenotype. Clinical reassessment of the patient and revision of the literature allowed us to refine the phenotype associated with
haploinsufficiency, including hyperkinetic movement disorder and flat angiomas as associated features. Interestingly, the patient also has an asymmetric face and choanal atresia and a novel
variant of the
gene.
We suggest that
-related ID syndrome may also predispose to the development of hyperkinetic movement disorders and flat angiomas. These features could therefore require specific management of this condition.
Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. ...Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.
Background:
Charcot–Marie–Tooth (CMT) is the most frequent group of inherited neuropathies and includes several heterogeneous phenotypes. Over 80 causative genes have been described so far. Variants ...in the microrchidia family CW-type zinc finger 2 (
MORC2
) gene have been described in several axonal polyneuropathy (CMT2) patients with childhood or adult onset. Occasionally more complex phenotypes with delayed milestones, severe hypotonia, intellectual disability, dystonic postures, pyramidal signs, and neuroimaging abnormalities have been reported.
Case Presentation:
We report on a patient with a
de novo MORC2
gene variant (c.1181A>G p.Tyr394Cys) with a history of developmental delay, axial hypotonia, progressive gait disorder with dystonic features, and intentional tremor. At the age of 8 years, he showed bilateral pyramidal signs (clonus, increased tendon reflexes, and Babinski sign) and bilateral pes cavus. The first neuroimaging performed at the age of 3 years demonstrated white matter abnormalities in the posterior periventricular zone, in the frontal lobes bilaterally and at the midbrain, stable during childhood and adolescence. Nerve conduction studies (NCS) were negative until the age of 15 years, when a sensory axonal neuropathy appeared. The association between pyramidal signs and neuropathy due to the
MORC2
gene variant is increasingly being highlighted, although a neuroradiological correlate is evident only in about half of the cases. Longitudinal nerve conduction velocity (NCV) are helpful to identify late-onset features and provide useful information for diagnosis in patients with rare neurogenetic disorders.
Conclusions:
Characterization of complex neurological disorders is important to delineate the expanding phenotypic spectrum of
MORC2
-related disease, to confirm if possible the pathogenicity of the variants and to deepen the genotype–phenotype correlation.
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