Familial periventricular nodular heterotopia

doi:10.1016/0387-7604(93)90073-H

Brain and Development

Volume 15, Issue 3, May–June 1993, Pages 237-241

https://doi.org/10.1016/0387-7604(93)90073-H Get rights and content

Abstract

We describe herein a 13-year-old girl, her 34-year-old mother and her 60-year-old grandmother who have periventricular heterotopic nodules. The mother has suffered from epileptic seizures since she was 15 years old, but the daughter and grandmother have had no epilepsy. They showed multiple uncalcified nodules on the lateral ventricular walls on CT. On MRI the intensity of the nodules was the same as that of the cerebral gray matter, suggesting heterotopia, and no other cerebral abnormalities were observed. Despite extensive examinations, neither have exhibited evidence of tuberous sclerosis. The periventricular nodular heterotopia observed in this family are a unique form of migration disorders, which may be caused by a dominant mutation.

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Direct Sanger sequencing of PCR amplicons containing the mutation verified variants in genes of interest. We identified mutations in known CH genes in four probands, including one proband with compound heterozygous mutations in MPDZ, the cause of autosomal recessive (AR) non-syndromic hydrocephalus type 2 (OMIM# 615219; Al-Dosari et al., 2013); two male probands with transmitted D-mis mutations in FLNA, the cause of X-linked dominant (XLD) periventricular heterotopia (OMIM# 300049; Kamuro and Tenokuchi, 1993; Sheen et al., 2004); and one proband with compound heterozygous mutation in CRB2 (Hydro122), the cause of a AR ventriculomegaly with cystic kidney disease (OMIM# 219730; Slavotinek et al., 2015). We determined a de novo mutation rate of 1.4 × 10−8 per base pair, with 1.09 de novo coding region mutations per proband (Table 1), consistent with expectation and previous work (Homsy et al., 2015; Timberlake et al., 2017; Ware et al., 2015).
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10⁻⁷), SMARCC1 (p = 8.15 × 10⁻¹⁰), and PTCH1 (p = 1.06 × 10⁻⁶). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10⁻⁴). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
Neuronal Migration
2018, Volpe's Neurology of the Newborn
As progenitor cells proliferate and differentiate into neurons and glia (see Chapter 5), these cells migrate to form the cerebral cortex in an elaborate and still not completely understood series of genetically influenced processes. Neurodevelopmental studies as well as disorders of brain development have informed our knowledge of these processes. In fact, the period of early migration overlaps with the proliferative period, and the period of late migration overlaps with later cortical organization (see Chapter 7). The disorders referred to as “disorders of migration” are so termed if migration is thought to be the first or principal process of development affected.
Ehlers-danlos syndrome: A cause of epilepsy and periventricular heterotopias
2014, Seizure
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This last mutation has been associated to PNH but in patients without EDS. Most cases of patients with PH present epilepsy66–71; the type of seizures is variable, even if majority of patients have partial attacks with temporo-parieto-occipital aura, and the severity may range from mild (with remission without anticonvulsant therapy) to intractable epilepsy. Age of onset is also variable from first year of life to adolescence.47,72–76
Ehlers–Danlos syndrome (EDS) comprises a variety of inherited connective tissue disorders that have been described in association with various neurological features. Until now the neurological symptoms have not been studied in detail; therefore, the aim of this review is to analyze the possible association between EDS, epilepsy and periventricular heterotopia (PH).
We have carried out a critical review of all cases of epilepsy in EDS patients with and without PH.
Epilepsy is a frequent neurological manifestation of EDS; generally, it is characterized by focal seizures with temporo-parieto-occipital auras and the most common EEG findings epileptiform discharges and slow intermittent rhythm with delta–theta waves. Epilepsy in EDS patients is usually responsive to common antiepileptic therapy; very few cases of drug resistant focal epilepsy requested surgical treatment, with favorable results in terms of outcome. Epilepsy is the most common presenting neurological manifestation associated with PH in EDS patients. Abnormal anatomic circuitries (including heterotopic nodules) could generate epilepsy in patients with PH.
Among the principal neurological manifestations, epilepsy and PH have a considerable importance and can influence the long-term evolution of these patients. We hypothesize that PH may determine the epileptic manifestations in patients with EDS; much remains to be learnt about the relationships between nodules and the epileptic manifestations in EDS syndrome.
Genetic Aspects of Human Epilepsy
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Genetic Disorders of Cerebral Cortical Development
2013, Emery and Rimoin's Principles and Practice of Medical Genetics
Periventricular nodular heterotopia
2007, Handbook of Clinical Neurology
Citation Excerpt :
The morphology of the overlying cortical areas is usually normal. This PNH type has been observed in first‐degree relatives from several families (DiMario et al., 1993; Kamuro and Tenokuchi, 1993; Huttenlocher et al., 1994; Oda et al., 1994), but it is also found in sporadic patients (Sheen et al., 2001). In the second type of bilateral PNH, i.e. bilateral and asymmetrical PNH, the heterotopia are made up by bilateral but clearly asymmetrical nodules in all cases (Fig. 11.1C).
Periventricular nodular heterotopia (PNH) is classified as a malformation of cortical development (MCD) because of impaired neuronal migration. It can be diagnosed in vivo by means of neuroimaging and is, together with focal cortical dysplasia, the most frequent human brain dysgenesis in most clinical studies addressing MCD features. MRI is the method of choice to detect the presence of PNH. The heterotopic nodules are isointense to cortical gray matter in all imaging sequences and they frequently bulge into the walls of lateral ventricles. On the basis of the MRI appearance, PNH cases have been classified in various ways in an attempt to relate different PNH types to specific etiologies. According to the more recent classification, three types of bilateral and two types of unilateral PNH can be distinguished. The first type is bilateral and symmetrical PNH, which is the best known and most studied PNH form for the frequent relation to filamin 1(FLN1) gene mutations. In bilateral and symmetrical PNH, multiple and contiguous nodules symmetrically line the entire extension of ventricular walls.

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Familial periventricular nodular heterotopia

Abstract

Brain Dev (Tokyo)

Exp Neurol

Brain Res

Band heterotopias: a newly recognized neuronal migration anomaly

Radiology