Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
Purpose of the review Subacute sclerosing panencephalitis (SSPE) is a rare, slowly progressive, and frequently fatal neurodegenerative disorder caused by measles virus. The risk of SSPE remains significant globally, with fluctuating incidence noted in in tandem with measles vaccine uptake. This review aims to explore the current global status of SSPE, its treatment, and preventive measures. Recent findings An increase in measles cases have been reported in various parts of the world for different reasons related to the regional context of the outbreak. With reduction in measles vaccine doses since the onset of the COVID-19 pandemic, the future risk of SSPE can only accelerate. In recent years, subsequent cases of SSPE have been reported in the period following documented measles outbreaks in different settings. Concomitantly, there have been efforts to evaluate the efficacy of immunomodulatory, antiviral, and anti-seizure therapies that could ameliorate the devastating effects of this disease. This review elucidates on these approaches and their limitations, reasons for poor vaccine coverage in low- and middle-income countries, as well as the possible solutions to the prevention of measles and eventual avoidance of SSPE. Summary Prevention of measles virus infection with the resultant sequelae would be the most effective strategy for the management of SSPE. This approach would be particularly important in low resource setting that currently bears the double burden of widespread communicable diseases and malnutrition.
Desmoplastic infantile gangliogliomas (DIGs) are uncommon supratentorial brain tumors with a usually good prognosis despite an aggressive radiological appearance. These tumors form part of a spectrum of desmoplastic infantile tumors that includes desmoplastic infantile astrocytomas. DIGs are classified as benign WHO grade I tumors of infancy. Non-infantile variants of this biologically benign intracranial neoplasm are rare, with only four previous case reports in the literature. We report two cases of non-infantile DIG diagnosed at our institution on the basis of clinical features, radiological appearance and histological findings.
CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is a recently described, rare neuroinflammatory disorder diagnosed by clinical symptoms involving the brain stem with a distinct pattern on neuroimaging and a perivascular T-lymphocyte infiltrate on brain biopsy. It is a condition usually described in adults in the fourth to fifth decade. We report a case of 13-year-old Indian boy who presented with recurrent episodes of ataxia and diplopia with onset at 7 years of age. He was investigated extensively to rule out infective, neoplastic, autoimmune, and demyelinating conditions over a span of 6 years. The diagnosis of CLIPPERS was entertained on the basis of clinico-radio-pathological correlation. Treatment with steroids and steroid-sparing agents, particularly methotrexate, seems to provide a promising outcome. With very few cases in literature so far, reporting of a larger case series with pediatric onset may expand it to CLIPPERS spectrum disorder.
This 27-year-old female presented with delay in motor milestones noted in infancy followed by slowly progressive motor disability starting at around 3 to 4 years of age and by speech difficulties appearing shortly thereafter.She was born at term from nonconsanguineous healthy parents. Family history was negative. She started to walk late, at 2 years of age, with an unsteady gait. She developed normal speech until around 3 years of age, when she could speak approximately three-to four-word sentences, after which she was noted to have started regressing in her motor followed by language milestones, which started with a stammer. She progressed over the next few years from being ataxic for a while followed by development of marked generalized dystonia, which has slowly progressed since then, along with significant oromotor dystonia. Speech impairment worsened to the point of unintelligibility in the subsequent years. Cognitively, she remained well with no evidence of deterioration. No seizures were ever noted. Furthermore, no visual impairment was observed. Her subsequent clinical course over the years is characterized by progressive spastic-dystonic tetraparesis with anarthria with marked oromotor dystonia.Findings on general physical examination when first observed by us at 18 years of age were normal with no obvious dysmorphic features. Neurological examination revealed extrapyramidal signs with severe generalized dystonia and rigidity. Speech was severely impaired because of oromandibular dystonia. The remainder of her other systemic examination was unremarkable with no evidence of organomegaly. Fundoscopy revealed no abnormality.Workup for her over several years included routine blood tests, alpha-fetoprotein, vitamin E, copper, and ceruloplasmin titers, which were negative. Metabolic workup, including blood and urine chromatography of amino acids and urinary organic acids, as well as peroxisomal function tests, were unremarkable. Neurophysiology included visual and brainstem auditory evoked potentials, electromyography, and nerve conduction velocities, which were all normal.MRI done at 3.5 years of age was reported to show patchy hyperintense lesions in the para ventricular deep white matter (WM) along the posterior part of bodies of the lateral ventricles and occipital horns on both sides on T2-weighted images. Repeat MRI brain at 13 and 25 years, apart from showing the previous WM changes, also showed bilateral hypointensities of the globus pallidus (GP) on T1-weighted images with corresponding low signal intensity on gradient-echo T2-weighted images, which was consistent with susceptibility effects from paramagnetic iron deposition. The susceptibility-weighted images (SWIs) done on the last scan revealed progression of the iron deposition involving the GP and spreading to the anterior SN. However, specific signal-intensity abnormalities, such as the "eye-of-the-tiger" sign, was not observed in any of the scans.In view of the above-described findings, DNA sequence analysis of the PANK2 gene was sent in suspic...
In this case report, we described a 15-year-old boy who presented with intermittent episodes of ataxia and diplopia since 6.5 years of age. Extensive workup done over several years was negative. Brain biopsy showed a neuroinflammatory disorder, and hence, differential diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, central nervous system (CNS) lymphoma, and small vessel CNS vasculitis were considered. A final diagnosis of familial hemophagocytic lymphohistiocytosis was made when the patient developed episodes of prolonged fever with pancytopenia much later in the course of illness and genetic workup revealed pathogenic mutations in the PRF1 gene.
Background:Juvenile Tay-Sachs disease is rarer than other forms of Tay-Sachs disease and is usually seen in children between the age of 2 and 10 years. Pyrimethamine as a pharmacological chaperone was used to increase β-hexosaminidase A activity in this patient.Patient:We describe a patient with Tay-Sachs disease from the Indian population, a juvenile case who presented with developmental regression starting at the age of three, initially with motor followed by language regression. She is currently incapacitated with severe behavioral issues.Conclusion:This brief communication gives an insight into the efficacy of pharmacological chaperones. It also describes two unreported mutations in hexosaminidase A gene from the Indian population. After commencing Pyrimethamine, though initial benefits with increase in levels corresponded with briefly halting the motor regression, the observed increase was only transient and not associated with discernible beneficial neurological or psychiatric effects.
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