Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B

In 2016, two research groups independently identified microdeletions and pathogenic variants in the lysine-specific histone methyltransferase 2B gene, KMT2B in patients with early-onset progressive dystonia. KMT2B-dystonia (DYT28) is emerging as an important and frequent cause of childhood-onset progressive generalised dystonia and is estimated to potentially account for up to 10% of early-onset generalised dystonia. Herein, we review variants in KMT2B associated with dystonia, as well as the clinical phenotype, treatment and underlying disease mechanisms. Furthermore, in context of this newly identified condition, we summarise our approach to the genetic investigation of paediatric dystonia.     

DYT2 screening in early-onset isolated dystonia

Background

Mutations in HPCA, a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term “DYT2 dystonia”. Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood.

Early onset primary dystonia

Dystonia is a syndrome characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. It is classified by age at onset, by distribution, and by aetiology. The aetiological classification distinguishes the following categories: primary, dystonia plus, secondary, heredo-degenerative and psychogenic dystonia.Primary dystonia is defined as clinical condition characterized by dystonia as the only neurological abnormality apart from tremor. Different genetic alterations and gene loci have been mapped in familial and sporadic patients. Early onset-primary dystonia (EO-PD) is the most severe form of primary dystonia, with clinical and genetic heterogeneity. It usually starts in one body part, subsequently spreads to involve other body regions with frequent generalization. DYT1 dystonia is transmitted as an autosomal dominant trait with reduced penetrance. The unique underlying mutation is a GAG deletion in the coding region of the TOR1A gene, located at chromosome 9q34. DYT16 dystonia is a novel recessive form of EO-PD, recently described in few patients, caused by mutations in the PRKRA gene located at chromosome 2q31. At least other two loci have been mapped, but there remains a large number of patients with EO-PD in whom no genetic alteration is discovered.     

Historical developments in children's deep brain stimulation

Background

Heterogeneous by the underlying pathobiology and clinical presentation, childhood onset dystonia is most frequently progressive, with related disability and limitations in functions of daily living. Consequently, there is an obvious need for efficient symptomatic therapies.

Myoclonus in fraternal twin toddlers: A French family with a novel mutation in the SGCE gene

Myoclonus dystonia is a rare movement disorder caused by mutations in the SGCE gene on chromosome 7q21 (DYT11) encoding the epsilon-sarcoglycan. Myoclonus is present in almost all patients and affects most often neck, trunk and upper limbs. Dystonia is present in about half of the patients. The mode of inheritance is autosomal dominant with variable clinical expression and maternal imprinting. Onset is usually in childhood or adolescence. Alcohol might relieve symptoms.We present a 33 month old girl and her twin brother with disabling involuntary jerky movements during intentional tasks. Family history of this French family was positive for the paternal uncle, his two daughters and the paternal great grandfather. Sequencing of the SGCE gene revealed a novel nonsense mutation c.942C > A (p.Tyr314X) in exon 7, confirming the diagnosis of myoclonus dystonia. Treatment with valproic acid significantly reduced myoclonic episodes and ameliorated life quality.     

Epilepsy in Aicardi–Goutières syndrome

BackgroundAicardi–Goutières syndrome (AGS) is a genetically determined early-onset encephalopathy with variable phenotype, including neurologic manifestations such as dystonia, spasticity, epileptic seizures, progressive microcephaly, and severe developmental delay. The aim of our study was the characterization of epilepsy, one of the most frequent and severe AGS manifestations, in molecularly confirmed patients.MethodsWe reviewed the medical records, EEG, and CT/MRI findings in 16 patients aged 1–22 years that carried AGS1-5 mutations.ResultsEpilepsy manifested in 12 (75%) patients and took a refractory course in 9 (56%). 4 (25%) patients presented with seizures in the first four weeks and 11 (69%) altogether in the first year of life. Spasms were reported in 3 (19%) patients, focal seizures in 4 (25%), myoclonic in 5 (31%), symmetric or asymmetric tonic in 11 (69%), generalized tonic–clonic in 3 (19%) and status epilepticus in 4 (25%). EEG recordings initially showed a slow and disorganized background, followed by a regional intermittent theta/delta slow, while obvious multifocal or generalized epileptic discharges were only observed at follow-up. None of these EEG features were specific of AGS. There was no discernible correlation between the genotype and epilepsy onset, seizure types and epilepsy evolution. Epilepsy severity did not correspond to neuroimaging pathology.DiscussionEpilepsy constitutes a cardinal feature of AGS, characterized by early onset, predominantly tonic semiology and a refractory course. The early discrimination of epileptic seizures from paroxysmal dystonia poses a challenge for neuropaediatricians, considering the initially inconspicuous or non-specific EEG findings. This study underlines the necessity of a more systematic serial evaluation of AGS patients using long-term video-EEG recordings.     

Semi-dominant X-chromosome linked learning disability with progressive ataxia,spasticity and dystonia associated with the novel MECP2 variant p.V122A: Akin to the new MECP2 duplication syndrome?

A novel X-chromosome linked phenotype is reported. Three affected males had learning disability in early childhood and subsequently developed progressive ataxia, dystonia, and spasticity with death at ages 9, 14 and 19 years. Two female obligate carriers had learning difficulties with psychosis in one case. A third, possible carrier had learning difficulties and epilepsy. A family study indicates that this inherited syndrome is most likely due to an unreported MECP2 variant, p.V122A, located in the methyl binding domain of the MECP2 protein. The clinical features are similar to those present in the newly reported MECP2 duplication syndrome. Non-progressive neuropsychiatric symptoms in female relatives of a male child with learning disability, ataxia and progressive spasticity may constitute a clue to inherited, MECP2 pathogenesis.     

Pediatric writer's cramp in myoclonus-dystonia: Maternal imprinting hides positive family history

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder with myoclonic jerks and dystonic contractions most frequently due to a mutation in the ?-sarcoglycan (SGCE, DYT11) gene. We describe two unrelated children with M-D (DYT11) who presented with writer's cramp. Due to maternal imprinting the family history appeared initially negative for M-D. In children with writer's cramp screening of the SGCE gene should be considered, even with a negative family history.     

Improvement in upper limb function in children with dystonia following deep brain stimulation

BackgroundChildhood dystonia can severely impact upper limb function. Deep Brain Stimulation (DBS) has been shown to be effective in reducing dystonic symptoms in childhood. Functional recovery following DBS is however not well understood.AimsTo explore changes in upper limb function following DBS in paediatric dystonia.MethodsUpper limb outcomes, using the Melbourne Assessment of Unilateral Upper Limb Function, are reported in 20 cases of childhood dystonia (unilateral n = 1, four limb n = 19) at 6 and 12 months following DBS.ResultsImprovement in at least in one upper limb was seen in the majority of cases (n = 17, 85%) at 12 months following DBS. Deterioration of scores in both upper limbs was seen in 3 children with progressive disorders. Grouping the children aetiologically, a significant improvement in the dominant hand was obtained for the primary dystonia/dystonia-plus group at both six (p = 0.018) and twelve months (p = 0.012). In secondary dystonia due to a static disorder, improvement was also seen at 6 (p = 0.043) and 12 months (p = 0.046) in the non-dominant hand. No significant change was found in the group of children with progressive disorders.ConclusionsDBS has the potential to alter upper limb function in children with primary and secondary dystonia. The dominant hand improved most in children with primary dystonias, with greater improvement in the non-dominant hand in secondary-static cases.     

Pyruvate dehydrogenase E2 deficiency: A potentially treatable cause of episodic dystonia

The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.     

Late onset epileptic spasms is frequent in MECP2 gene duplication: Electroclinical features and long-term follow-up of 8 epilepsy patients

Mutation of the X-linked methyl CpG binding protein 2 (MECP2) has been first identified as the cause of Rett syndrome. More recently, MECP2 gene duplication syndrome has been identified in males. The MECP2 duplication syndrome is characterized by severe mental retardation, infantile hypotonia, progressive spasticity and recurrent infections. Epileptic seizures are inconstant but poorly described. The aim of the study is to describe the electroclinical features of epilepsy in MECP2 duplication patients in order to refine the epilepsy phenotype and its evolution.MethodsWe conducted a retrospective study in four child neurology departments in France. Eight boys with a MECP2 gene duplication and epilepsy were retrospectively studied. We evaluated both clinical and electroencephalographic data before seizure onset, at seizure onset and during the follow-up.ResultsThe patients started seizures at the median age of 6 years (range: 2.5–17 years). Half exhibits late onset epileptic spasms while the other exhibit either focal epilepsy or unclassified generalized epilepsy. Before seizure onset, EEGs were abnormal in all patients showing a slowing of the background or a normal background with fast activities, while EEG performed in epileptic patients, showed a slowing of the background in 6/8 and localized slow or sharp waves in 7/8. Most patients (6/8) have evolved to drug resistant epilepsy.ConclusionAlthough late onset epileptic spasms are common in patients with MECP2 duplication, no specific electroclinical phenotype emerges, probably due to genetic heterogeneity of the syndrome. Further studies are needed to individualize specific epileptic subtype in larger cohort of patients.     

Natalizumab treatment in pediatric multiple sclerosis: A case report

Pediatric multiple sclerosis (MS) with manifestations before 16 years of age occurs in 0.4–10.5% of whole MS population. The initial course of the disease is relapsing–remitting with a relapse rate generally higher than that of adults, less than 3% have a primary progressive form. Some recent reports have shown that Interferon β (IFNβ) has a strong effect in reducing the relapse rate in children with MS and is well tolerated.We report a 12-year-old girl with MS and a high relapse rate from the onset. Frequent magnetic resonance imaging (MRI) detected persisting inflammatory activity and increase of lesion burden. She continued to present acute relapses and progression of disability in spite of a treatment with IFNβ-1a at different dosages and the addition of pulse IV steroid treatment. Then, we opted for Natalizumab treatment, recently approved as a monotherapy for patients with MS who experienced inadequate response to other disease modifying therapies and never used till now in pediatric MS. Our patient showed a complete response to Natalizumab with clinical and MRI suppression of disease activity.     

Phenotypic and genotypic variability in Alpers syndrome

BackgroundAlpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1.AimsTo investigate the phenotypic–genotypic correlations in Alpers syndrome and to identify potential differences among patients with Alpers syndrome with or without pathogenic POLG1 mutations.MethodsPatients with the phenotype of Alpers syndrome who were referred to our pediatric hospital during 1984–2007 and were diagnosed with mitochondrial encephalomyopathy underwent further biochemical, morphological and genetic investigations.ResultsA total of 19 patients were included in the study, of whom six had pathogenic POLG1 mutations including a novel mutation (c.907 G > A, p.Gly303Arg). Complete mtDNA sequencing in the subgroup without POLG1 mutations showed 5 novel and 5 very rare mtDNA variants considered as rare polymorphisms. Compared to POLG1(?) patients, the POLG1(+) patients more frequently had seizures at onset, which often became refractory. Ataxia and stroke-like episodes were much more common, while microcephaly and spasticity were encountered almost solely in the POLG1(?) group. Hepatic and ophthalmological involvement developed in 79% and 88% of patients, respectively. Most of the patients in both groups had predominant deficiency of complex I. In addition to the major degenerative changes in the cerebral cortex, the basal ganglia, thalamus and white matter were also involved to variable extent.ConclusionAlpers syndrome is a heterogeneous syndrome that should be considered in patients with early-onset progressive cortical encephalopathy regardless of liver involvement. The phenotype is different depending on the presence or absence of POLG1 mutations.     

Pharmacological strategies in the idiopatic pulmonary fibrosis of children

Idiopathic pulmonary fibrosis is characterized by radiographically evident interstitial infiltrates and progressive dyspnea with rapid decline of overall lung functions. The clinical course of this disease is highly variable; however, its prognosis remains poor without adequate and prompt therapeutical support. Due to the fact that barely a quarter of patients responds to steroids alone, cytostatics are often prescribed simultaneously with low dose corticosteroids in the pediatric age too. Cytokine or anti-cytokine therapy and the role of new antifibrotic drugs are still at the experimental stage of definition and will be discussed in the following review.     

SLC2A1 mutations are a rare cause of pediatric-onset hereditary spastic paraplegia

SLC2A1 mutations cause glucose transporter type 1 deficiency syndrome, whose phenotypic spectrum is a continuum, ranging from classic to variant phenotypes, the latter accounting for about 10% of cases. Very few SLC2A1-mutated patients with a spastic paraplegia phenotype have been reported so far, and they are associated with paroxysmal choreo-athetosis (i.e., DYT9). The authors describe two sporadic children with pure and complex hereditary spastic paraplegia (HSP) without paroxysmal non-epileptic movement disorders harboring heterozygous de novo SLC2A1 pathogenic variants. These patients have been identified by a targeted panel for HSP among 140 pediatric- and adult-onset unrelated cases with pure and complex HSP, thus indicating an overall prevalence of 1.4% of SLC2A1 mutations, which increases to 3% if only pediatric-onset patients are considered. The implications of these findings in the diagnostic work-up of HSP patients are discussed.     

Infantile onset progressive cerebellar atrophy and anterior horn cell degeneration--a late onset variant of PCH-1?

Despite major recent advances in our understanding of developmental cerebellar disorders, classification and delineation of these disorders remains difficult. The term pontocerebellar hypoplasia is used when there is a structural defect, originating in utero of both pons and cerebellar hemispheres. The term olivopontocerebellar atrophy is used when the disorder starts later in life and the process is a primary degeneration of cerebellar neurons. Pontocerebellar hypoplasia type 1 is associated with spinal anterior horn cell degeneration, congenital contractures, microcephaly, polyhydramnion and respiratory insufficiency leading to early death. However, anterior horn cell degeneration has also been described in cases with later onset pontocerebellar atrophy and recently the spectrum has even been further extended to include the association of anterior horn cell degeneration and cerebellar atrophy without pontine involvement. We describe two siblings from a consanguineous Moslem Arabic family who presented with progressive degeneration of both the cerebellum and the anterior horn cells. The patients presented after 1 year of age with a slow neurodegenerative course that included both cognitive and motor functions. There is considerable phenotypic variability; the sister shows a much milder course. Both children are still alive at 6 and 9 years. The sister could still crawl and speak two word sentences at the age of 3 years while the brother was bedridden and only uttered guttural sounds at the same age. Our cases further extend the phenotype of the cerebellar syndromes with anterior horn cell involvement to include a childhood onset and protracted course and further prove that this neurodegenerative disorder may start in utero or later in life.     

Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype–phenotype correlations and diagnostic guidelines based on new cases and overview of the literature

Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases.Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases. Signs of antenatal onset of disease present at birth were common in all PCH1 sub-types except in the homozygous p.D132A/EXOSC3 patients. The PCH1sub-types with early death (between ages 1 day and 17 months), seen in patients with p.G31A/EXOSC3 or SLC25A46 mutations have a SMA type 1-like clinical presentation but with global developmental delay, visual and hearing impairment, with or without microcephaly, nystagmus and optic atrophy. Mutations with milder presentation (homozygous p.D132A/EXOSC3 or VRK1) may display additionally signs of upper motor neuron impairment, dystonia or ataxia and die at age between 5 and 18 years. Other EXOSC3 mutations and EXOSC8 cases are intermediate - SMA type 1-like presentation, spasticity (mostly in EXOSC8) and death between 3 months and 5 years. There is no correlation between neurological onset and duration of life. We add marble-like skin and congenital laryngeal stridor as features of PCH1. We show that imaging signs of cerebellar and pontine hypoplasia may be missing early in infancy. EMG signs of anterior horn neuronopathy may be missing in PCH1 patients with SLC25A46 mutations. Thus, there is considerable phenotypic variability in PCH1, with some cases being more SMA-like, than PCH-like. Detailed clinical evaluation and ethnicity background may guide genetic testing and subsequent genetic counseling.     

Clinical and immunological profile of systemic lupus erythematosus

Pediatric onset systemic lupus erythematosus (SLE) is not uncommon and female to male ratio varies. Pediatric SLE patients have more severe disease at onset, higher rates of organ involvement and more aggressive clinical course than adults. We compared the clinical and immunological parameters among pediatric SLE and adult SLE from Western India. Twenty five children and 60 adult patients fulfilling American College of Rheumatology SLE criteria were included. Anti-nuclear antibodies, anti-dsDNA and complement (C3, C4) levels were tested. Of 25 pediatric SLE patients studied, 24% showed CNS involvement vs. 8.3% in adults SLE (P=0.0499). Lupus nephritis was seen in 75% adult patients vs. 52% among children. Hepatosplenomegaly was noted more among adult SLE 26.8% vs 12% among children. Alopecia was an exclusive features among adult SLE.     

Hallervorden-Spatz syndrome with acanthocytosis

The case of a female patient with infantile onset of progressive dystonia, disturbance of gait and dysarthria is presented. At age 7, the diagnosis of Hallervorden-Spatz disease was established by clinical findings including retinal pigment degeneration, basal ganglia hyperdensity on CT, and the rare association of acanthocytosis. The clinical course was followed over 15 years until the patient's death.     

Relevance of viral phenotype in the early AIDS outcome of pediatric HIV-1 primary infection

In infants the clinical course of HIV-1 infection is bimodal, differing considerably from that of adults. The effect of HIV-1 phenotypic features and plasma viral load on the clinical course of infection has been well established in adults, whereas in children it remains controversial. The aim of this study was to prospectively evaluate the effect of HIV-1 replication phenotypes during the first year of primary infection in the development of premature immunosuppression and early pediatric AIDS. In 62 vertically infected children replication rates of HIV-1 isolates from primary cultures and syncytium-inducing capability in MT-2 cell line were evaluated, together with plasma viral load. It was observed that rapid replication rate and syncytium-inducing phenotype accelerate the early onset of pediatric AIDS (p = 0.02 and p = 0.04, respectively). Rapid replication kinetics was the only significantly independent variable for early clinical outcome (risk ratio, 2.48; p = 0.02). Both viral properties contributed to rapid CD4+ T-cell depletion (p = 0.05 for rapid replication rate, p = 0.01 for syncytium-inducing viral phenotype). Plasma viral burden higher than 5.5 log(10) copies/mL after 6 mo of age tended to be associated with disease progression. In conclusion, initial HIV-1 biologic features in pediatric primary infection by vertical transmission may influence the progression to early immunosuppression and development of AIDS.