Clinical characteristics and genetic analysis of a case with adult neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic variants in a patient with adult ceroid lipofuscinosis neuronal type 7 (ACLN7).@*METHODS@#A female patient diagnosed with ACLN7 in Henan Provincial People's Hospital in June 2021 was selected as the study subject. Clinical data, auxiliary examination and result of genetic testing were retrospectively analyzed.@*RESULTS@#The patient, a 39-year-old female, has mainly presented progressive visual loss, epilepsy, cerebellar ataxia and mild cognitive decline. Neuroimaging analysis has revealed generalized brain atrophy, prominently cerebellum. Fundus photography has revealed retinitis pigmentosa. Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells. Whole exome sequencing revealed that she has harbored compound heterozygous variants of the MSFD8 gene, namely c.1444C>T (p.R482*) and c.104G>A (p.R35Q). Among these, c.1444C>T (p.R482*) was a well established pathogenic variant, while c.104G>A (p.R35Q) was a missense variant unreported previously. Sanger sequencing confirmed that the daughter, son and elder brother of the proband have respectively carried heterozygous c.1444C>T (p.R482*), c.104G>A (p.R35Q), and c.104G>A (p.R35Q) variants of the same gene. The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7.@*CONCLUSION@#Compared with previously reported cases, this patient has the latest onset of the disease with a non-lethal phenotype. Her clinical features have involved multiple systems. Cerebellar atrophy and fundus photography may be indicative of the diagnosis. The c.1444C>T (p.R482*) and c.104G>A (p.R35Q) compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.

Lipofuscinosis ceroidea neuronal 6 (enfermedad Kufs tipo A): Reporte de caso en Colombia / Neuronal ceroid lipofuscinosis 6 (Kufs disease Type A): Case report from Colombia

RESUMEN INTRODUCCIÓN: Las lipofuscinosis ceroideas neuronales (CLN) son un grupo de enfermedades neurodegenerativas de inicio generalmente en la infancia, caracterizadas por acumulación intracelular de material de almacenamiento autofluorescente. En la última década se han identificado 14 formas de CLN con mutaciones en 13 genes (CLN1-CLN14), en la CLN9 no se ha identificado aún el gen. Los pacientes con mutaciones en el gen CLN6 localizado en el cromosoma 15q21-23 presentan tres tipos de variantes clínicas: CLN6 infantil tardía, con presentación entre 18 meses a 8 años, las variantes Kufs tipo A y Kufs tipo B de inicio en adolescentes y adultos. REPORTE DE CASO: Se presenta el caso de un paciente con epilepsia generalizada de inicio en la edad adulta, que ingresa a valoración en primera ocasión, con resonancia magnética cerebral con atrofia cortical leve; la enfermedad se inició a los 14 años con déficit cognitivo lentamente progresivo, sin compromiso visual; con posterior identificación genética de una variante patogénica en el gen CLN6, con un conjunto de la variante clínica Kufs tipo A de lipofuscinosis ceroidea neuronal 6 (CLN6). DISCUSIÓN: Este es el primer reporte de CLN6 con variante clínica Kufs tipo A en Colombia. Con el advenimiento de técnicas genéticas se pueden hacer diagnósticos específicos de CLN6, a partir de la clínica y sospecha diagnóstica; utilizando métodos no invasivos.

ABSTRACT INTRODUCTION: Neuronal ceroid lipofuscinosis (CLN) is a group of neurodegenerative diseases generally with onset in childhood, characterized by intracellular accumulation of autofluorescent storage material. In the last decade, 14 forms of CLN have been identified with mutations in 13 genes (CLN1-CLN14), in CLN9 the gene has not yet been identified. Patients with mutations in the CLN6 gene located on chromosome 15q21-23 present three types of clinical variants: late childhood CLN6, presenting between 18 months to 8 years, the Kufs type A and Kufs type B variants of onset in adolescents and adults. CASE REPORT: We present the case of a male patient with generalized epilepsy of onset in adulthood, who was admitted for evaluation the first time, with brain magnetic resonance imaging with mild cortical atrophy; he started at age 14 with slowly progressive cognitive deficit, without visual compromise; with subsequent genetic identification of a pathogenic variant in the CLN6 gene, jointly presenting the clinical variant Kufs type A of neuronal ceroid lipofuscinosis 6 (CLN6). DISCUSSION: This is the first report of CLN6 with Kufs type A clinical variant in Colombia. With the advent of genetic techniques, specific diagnoses of CLN6 can be made, based on the clinical and suspected diagnoses; using non-invasive methods.

Genetic study of a family of neuronal ceroid lipofuscinosis caused by a heterozygous mutation of gene / 浙江大学学报·医学版

OBJECTIVE@#To analyze the genetic cause of a family with autosomal recessive neuronal ceroid lipofuscinoses (NCL).@*METHODS@#The proband was screened for mutations within the coding region of the candidate genes through high-throughput targeted sequencing. Potential causative mutations were verified by PCR and Sanger sequencing in the proband and his parents. RT-PCR and TA clone sequencing were performed to investigate whether the mRNAs were abnormally spliced.@*RESULTS@#The sequencing results revealed compound heterozygous mutations of :c.486+2T>C and c.486+4A>T, which were respectively inherited from his parents. RT-PCR and TA cloning sequencing suggested that the mRNAs were abnormally spliced in two forms due to both mutations.@*CONCLUSIONS@#The compound heterozygous mutations of :c.486+2T>C and c.486+4A>T are possibly the genetic causes of the NCL family. Detection of the novel mutation has extended mutation spectrum of .

CLN6 Mutation in a Patient with Progressive Myoclonus Epilepsy / 대한소아신경학회지

Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders, which are caused by the accumulation of lipopigment in lysosomes. Variant forms of late infantile NCLs (vLINCLs) characterized by a later onset of seizures and visual impairment (3–8 years) than in the classic form (2–4 years) are caused by mutations of the gene encoding ceroid lipofuscinosis neuronal protein 6 (CLN6). In a girl with progressive myoclonus epilepsy, we found heterozygous variants of CLN6 (NM_017882.2; NP_060352.1): c.296A>G (p.Lys99Arg) and c.307C>T (p.Arg103Trp). They were identified with whole-exome sequencing and verified with Sanger sequencing. At 7 years and 9 months, our patient had developed multiple types of seizures, prominent myoclonus with photosensitivity, regression in motor and language skills, pyramidal and extrapyramidal signs, and brain atrophy in brain images, all of which were progressive and were compatible with vLINCLs. However, this first Korean report shows no visual impairment, which resembles the previously reported Japanese case.

Retinal function in patients with the neuronal ceroid lipofuscinosis phenotype / Estudo da função retiniana em pacientes com o fenótipo da lipofuscinose ceróide neuronal

ABSTRACT Purpose: To analyze the clinical features, visual acuity, and full-field electroretinogram (ERG) findings of 15 patients with the neuronal ceroid lipofuscinosis (NCL) phenotype and to establish the role of ERG testing in NCL diagnosis. Methods: The medical records of five patients with infantile NCL, five with Jansky-Bielschowsky disease, and five with juvenile NCL who underwent full-field ERG testing were retrospectively analyzed. Results: Progressive vision loss was the initial symptom in 66.7% of patients and was isolated or associated with ataxia, epilepsy, and neurodevelopmental involution. Epilepsy was present in 93.3% of patients, of whom 86.6% presented with neurodevelopmental involution. Fundus findings ranged from normal to pigmentary/atrophic abnormalities. Cone-rod, rod-cone, and both types of dysfunction were observed in six, one, and eight patients, respectively. Conclusion: In our study, all patients with the NCL phenotype had abnormal ERG findings, and the majority exhibited both cone-rod and rod-cone dysfunction. We conclude that ERG is a valuable tool for the characterization of visual dysfunction in patients with the NCL phenotype and is useful for diagnosis.

RESUMO Objetivo: Analisar o quadro clínico, a acuidade visual e o eletrorretinograma de campo total (ERG) de 15 pacientes com o fenótipo da lipofuscinose ceróide neuronal (LCN), estabelecendo o papel do eletrorretinograma no seu diagnóstico. Métodos: Eletrorretinograma foi realizado em 5 pacientes com lipofuscinose ceróide neuronal infantil, 5 com doença de Jansky-Bielschowsky e 5 com lipofuscinose ceróide neuronal juvenil sendo feita uma análise retrospectiva dos registros médicos. Resultados: A perda progressiva da acuidade visual foi o sintoma inicial em 66,7%; isolada ou associada à ataxia, epilepsia e involução do desenvolvimento neuropsico motor. Epilepsia foi o sintoma inicial em 93,3% e 86,6% apresentaram involução do desenvolvimento neuropsicomotor. Achados fundoscópicos variaram de normal a alterações pigmentares/atróficas. Disfunção de cone-bastonete foi constatada em 6 pacientes, bastonete-cone em 1 e em 8 pacientes observou-se disfunção proporcional de ambos os sistemas. Conclusão: O eletrorretinograma foi alterado em todos os pacientes, e o achado mais frequente foi o comprometimento de cones e bastonetes. O eletrorretinograma constitui, portanto, uma ferramenta valiosa para caracterizar a disfunção visual em pacientes com o fenótipo da lipofuscinose ceróide neuronal, contribuindo para seu diagnóstico.

Late Infantile Neuronal Ceroid Lipofuscinosis in a Filipino child with epilepsy and progressive neurodegeneration

@#The neuronal ceroid lipofuscinoses correspond to a group of disorders characterized by neurodegeneration and intracellular buildup of auto-flourescent lipopigment (ceroid lipofuscin). They are classified by age of onset into infantile, late infantile, juvenile and adult forms. Among these, the late infantile type is caused by mutations in tripeptidyl peptidase 1 (TPP1) gene and is characterized by age of onset between 2-4 years, seizures, early progressive cognitive impairment and visual loss. Our patient is a 4-year-old girl who presented at 2 years and 10 months old with seizures followed by ataxia, regression of skills and eventual visual decline. TPP1 enzyme activity was below normal for age. This report aims to increase the awareness of physicians on the cluster of symptoms characteristic of this disorder which will help facilitate early diagnosis and prompt institution of appropriate management.

Lipofuscinosis ceroidea neuronal infantil tardía (Jansky- Bielchowsky). Estudio de casos / Late-Infantile Neuronal Ceroid Lipofuscinoses (Jansky-Bielschowsky Disease): a Study of a Series of Cases

Introducción: La lipofuscinosis ceroidea neuronal constituye el grupo de desordenes genéticos neurodegenerativos de depósito más común en la infancia, afecta a niños, adultos jóvenes y tiene herencia autosómica recesiva. Objetivo: Presentar un estudio de casos clínicos de 8 pacientes con lipofuscinosis ceroidea neuronal infantil tardía. Metodología: Estudio de casos clínicos de pacientes cuyos diagnósticos de lipofuscinosis ceroidea neuronal infantil tardía es propuesto a través del cuadro clínico: semiología de las crisis epilépticas, cronología de la aparición de las manifestaciones visuales, motoras, cognitivas y regresión en el neurodesarrollo. Resultados: Caso 1. Niño de 6 años de edad, con pérdida progresiva de la visión desde los 3 años llegando a la amaurosis, epilepsia desde los 4 años, ataxia y dificultades motoras y cognitivas a los 5 años. Electroencefalograma interictal patrón epiléptico. Resonancia Magnética de cráneo con atrofia de cerebro y cerebelo e indemnidad de ganglios basales. Casos 2, 3, 4 y 5 muestran el carácter hereditario, presentándose en 2 miembros de la misma familia. Caso 6, de inicio tardío, fue clasificada posteriormente como tipo 3, forma Juvenil, por análisis mutacional. Caso 7, convulsiones como síntoma inicial a los 3 años, resaltando las dificultades conductuales en el relacionamiento con sus pares lo que motiva la consulta con especialista. Caso 8, con una evolución rápida hacia el deterioro global. Conclusiones: La LCN es una entidad a tener en cuenta ante un paciente entre los 2 y 4 años que presente epilepsia refractaria, regresión del desarrollo y compromiso visual. La presencia de epilepsia mioclónica orienta la búsqueda de la etiología, modifica la conducta terapéutica. No existe aún un tratamiento definitivo para esta enfermedad, el manejo se dirige desde las fases iniciales a mejorar la calidad de vida del paciente y la de su familia con medidas generales y de sostén.

Perioperative care of a patient with neuronal ceroid lipofuscinoses

The neuronal ceroid lipofuscinoses [NCL] are a group of inherited, autosomal recessive, and progressive neurodegenerative diseases, which result from an enzymatic defect or the deficiency of a transmembrane protein, leading to the accumulation of lipopigments [lipofuscin] in various tissues. NCL results in the impairment of function in several end-organs including the central nervous system with loss of cognitive and motor function, myoclonus, and intractable seizures. Additional involvement includes the cardiovascular system with arrhythmias and bradycardia as well as impairment of thermoregulation leading to perioperative hypothermia. Given the complexity of the end-organ involvement and the progressive nature of the disorder, the anesthetic care of such patients can be challenging. Till date, there are a limited number of reports regarding the anesthetic management of patients with NCL. We present an 18-year-old patient with NCL who required anesthetic care during replacement of a vagal nerve stimulator. Previous reports of anesthetic care for these patients are reviewed, the end-organ involvement of NCL discussed, and options for anesthetic care presented

Juvenile neuronal ceroid-lipofuscinosis: clinical and molecular investigation in a large family in Brazil / Lipofuscinose ceróide neuronal juvenil: investigação clínica e molecular em uma família grande no Brasil

OBJECTIVE: Juvenile Neuronal Ceroid-Lipofuscinosis (JNCL, CLN 3, Batten Disease) (OMIM #204200) belongs to the most common group of neurodegenerative disorders of childhood. We report the clinical data and molecular analysis of a large Brazilian family. METHOD: Family composed of two consanguineous couples and thirty-two children. Clinical data of ten JNCL patients and molecular analyses on 13 participants were obtained. RESULTS: The large 1.02 kb deletion was detected. The most severe phenotype, with autistic behavior, tics and parkinsonism was seen in a 12-year-old female and a milder phenotype in a 14-year-old male. Nyctalopia was the first symptom in one deceased child. The visual loss of six patients has been first observed in the school and not at home. CONCLUSION: The report highlights the phenotypical intrafamily variation in 10 affected children of this family. The molecular investigation of this large family in our metabolic center turned possible the diagnosis, right approach and genetic counseling.

OBJETIVO: Lipofuscinose Ceróide Neuronal Juvenil (JNCL, CLN 3, Doença de Batten) (OMIM # 204200) pertence ao grupo mais comum de doenças neurodegenerativas na infância. É causada por mutações no gene CLN3, com padrão de herança recessiva. A deleção de 1,02 kb é a mutação mais comum. Relatamos os dados clínicos e análise molecular de uma família consanguínea numerosa. MÉTODO: Família composta por dois casais consanguíneos e trinta e duas crianças. Foram obtidos dados clínicos de dez pacientes e análises moleculares de 13 participantes. RESULTADOS: Foi detectada deleção de 1,02 kb. O fenótipo mais grave, com comportamento autista, tiques e parkinsonismo foi visto em uma paciente do sexo feminino de 12 anos e o fenótipo mais leve em um paciente do sexo masculino de 14 anos. Nictalopia foi o primeiro sintoma de uma criança falecida. A perda visual de seis pacientes foi observada pela primeira vez na escola e não em casa. CONCLUSÃO: Destaca-se a variação fenotípica intrafamiliar em 10 pacientes. A investigação molecular desta família numerosa tornou possível o diagnóstico, a abordagem correta e aconselhamento genético.

Lipofuscinose ceróide neuronal: achados clínicos e neurorradiológicos / Neuronal ceroid lipofuscinosis: clinical and neuroradiological findings

Lipofuscinose ceróide neuronal (LCN) constitui um grupo de doenças neurodegenerativas caracterizadas pelo depósito anormal de uma substância autofluorescente de lipopigmentos, que lembra ceróide e lipofuscina, dentro dos lisossomos dos neurônios e outros tipos de células. Os principais subtipos fenotípicos, baseando-se na idade de início, curso clínico e morfologia ultraestrutural, são classificados em formas infantil, infantil tardia, juvenil e adulta. Seis genes associados a lipofuscinose ceróide foram identificados e aproximadamente 150 mutações também são descritas. Relatamos sete pacientes com LCN baseados na história clínica, achados neurorradiológicos e patológicos avaliados na Rede Sarah de Hospitais de Reabilitação - Fortaleza - Ceará - Brasil. Cinco casos foram confirmados com biópsia de pele, sendo dois casos irmãos de pacientes confirmados. O diagnóstico precoce de LCN, uma doença com herança autossômica recessiva, é mandatório para aconselhamento genético e prevenção de outros casos na família. Os achados de imagem podem contribuir no diagnóstico diferencial.

The neuronal ceroid lipofuscinoses (NCL) are a group of neurodegenerative disorders, characterized by abnormal storage of an autofluorescent substance of lipopigments, resembling ceroid and lipofuscin, within lysosomes of neurons and other types of cells. The main phenotypic subtypes have been established on the basis of age of onset, clinical course, and ultra structural morphology, and classified as infantile, late infantile, juvenile and adult forms. Six genes have been associated with human NCL and approximately 150 mutations have been described. The aim of this study is to report the clinical, neuroradiological, and morphological characteristics of seven patients evaluated at Sarah Network of Hospitals for Reabilitation - Fortaleza - Ceará - Brazil. Five cases were histopathologically confirmed with skin biopsy and two were siblings of confirmed patients. An early diagnosis of NCL, an autosomal recessive disease, is mandatory for genetic counseling and to avoid further cases in the family. Imaging findings can contribute to the differential diagnosis.

Two novel mutations in palmitoyl-protein thioesterase gene in two Chinese babies with infantile neuronal ceroid lipofuscinosis / 中华儿科杂志

<p><b>OBJECTIVE</b>To search for possible novel mutations in palmitoyl-protein thioesterase 1 (PPT1) gene in two Chinese babies with infantile neuronal ceroid lipofuscinosis (INCL).</p><p><b>METHODS</b>Two probands with INCL, confirmed clinically and pathologically, were used for mutation search in PPT1 gene. Onset of the disease occurred before the age of 1 year and they mainly showed progressive mental and motor retardation. The 9 coding exons and their flanking intron sequences of palmitoyl-protein thioesterase 1 (PPT1) gene were amplified by using PCR and sequenced. The parents of proband 1 were also examined.</p><p><b>RESULTS</b>One splicing mutation and two missense mutations were identified in the two probands: the proband 1 carrying a compound heterozygous mutation of a IVS1 + 1G-->A mutation in intron 1 and a c550G-->A mutation in exon 6 leading to the amino acid substitution of E184K. Additionally, the parents of the proband 1 also harbored one of the mutations of the patient, respectively. The proband 2 carrying a homozygous mutation of c272A-->C in exon 3, which resulted in the amino acid substitutions of Q91P.</p><p><b>CONCLUSIONS</b>The IVS1 + 1G-->A mutation and Q91P mutation are novel mutations, which lead to INCL. The genetic abnormalities of PPT1 in Chinese patients may not be completely the same as those in the patients of other regions of the world.</p>

Lipofuscinosis ceroidea neuronal / Neuronal Ceroid-Lipofuscinosis

Las lipofuscinosis ceroideas neuronales son un grupo de enfermedades neurodegenerativas con herencia autosómica recesiva, que se presentan principalmente en la infancia y adolescencia, caracterizadas por síntomatología variable que incluye convulsiones, deterioro cognitivo, pérdida visual y/o atrofia cerebral. En los últimos años se han realizado extraordinarios progresos en la tipificación y el conocimiento de los mecanismos patogénicos involucrados en estas enfermedades.

Dificuldades no diagnóstico clínico e eletrencefalográfico de lipofuscinose ceróide neuronal / Pitfalls in the clinical and electroencephalographic diagnosis of ceroid lipofuscinosis

Tradicionalmente, as lipofuscinoses ceróides neuronais (LCN) eram classificadas de acordo com a idade de início e características clínicas em quatro grandes grupos. Recentemente, os estudos genéticos possibilitaram uma classificação mais pormenorizada dessa entidade em oito formas, permitindo o diagnóstico mais preciso de casos previamente considerados atípicos. Por outro lado, foi demonstrado que mutações de um mesmo gene poderiam ser responsáveis por grande variedade de fenótipos clínicos. O objetivo deste estudo é apresentar dois irmãos com achados clínicos e eletrencefalográficos compatíveis com a forma juvenil de LCN mas com alterações ultra-estruturais características da forma infantil tardia dessa doença. Os achados eletrencefalográficos auxiliam no diagnóstico da LCN, mas pouco contribuem na sua classificação.

Enfermedad de Jansky-Bielschowsky. Reporte de un caso / Bielschowsky-Jansky disease. A case review

Las lipofuscinosis ceroide neuronal constituyen el grupo más frecuente de trastornos neurodegenerativos de los niños y comprenden tres trastornos que se heredan con carácter autosómico recesivo y se caracterizan desde el punto de vista clínico por crisis mioclónicas, deterioro intelectual y pérdida progresiva de la visión. Se diagnostica basándose en los datos clínicos y en la exploración neuroftalmológica. En este trabajo se presenta un caso de un niño de 10 años de edad que ingresó en el Hospital General Roberto Rodríguez con la variedad clínica de lipofuscinosis ceroide neuronal infantil tardía. Se describen las características clínicas del paciente, así como los exámenes neuroftalmológicos realizados.

A Case of Late Infantile Neuronal Ceroid Lipofuscinosis

Neuronal ceroid lipofuscinosis, which is also known as Batten-Bielschowsky disease, is a group of neuro degenerative disorders, associated with various progressive symptoms including seizures, dementia, visual loss and cerebral atrophy. We experienced a case of late infantile neuronal ceroid lipofuscinosis in a 6-year-old boy who had progressive myoclonic seizures, ataxia, rapid psychomotor deterioration and visual loss. Photic stimulation at 2 to 5 Hz elicited a discrete spike and wave discharges in the occipital region on an electroencephalogram. Magnetic resonance imaging of the brain showed generalized cerebral and cerebellar atrophy. An electron microscopic examination of the skin revealed characteristic curvilinear inclusion bodies. An optic fundoscopy revealed a devastated retina and severe optic atrophy. We report this case with the brief review of related literature.

A Case of Late Infantile Neuronal Ceroid Lipofuscinosis that was Diagnosed by Characteristic EEG Findings / 대한간질학회지

Neuronal ceroid lipofuscinoses (NCL) are the most common childhood neurodegenerative disorders. Clinical features include seizures, blindness, psychomotor deterioration, the age of onset differ for each NCL type. Diagnosis of late infantile NCL relies on the characteristic clinical presentation, electrophysiological and neuroradiological findings, and identification of the ultrastructural abnormalities. The Photoparoxsmal response provide diagnostic clues to an atypical case of Infantile NCL in which results of extraneuronal biopsies were negative and MRI findings resembles leukodystrophy. Photic stimulation with 2 to 5 Hz activity elicited discrete spike and wave discharges in the occipital region on electroencephalogram and no sleep spindles are present. In patients with rapid neurologic deterioration, diagnosis of NCL should be considered and an EEG must be performed using photic stimulation to look for characteristic findings.

A Case of Adult Neuronal Ceroid-Lipofuscinosis, Proven by Brain Biopsy

A 20-year-old woman was admitted because of intractable seizures, myoclonus, gait ataxia, and severe intellectual deterioration with age of onset at 16 years. She had no family history of neurological disease. A thorough laboratory investigation was unremarkable. Brain MRI showed generalized cerebral and cerebellar atrophy. Interictal EEG showed intermittent generalized polyspike and waves, maximum on the bilateral parieto-occipital areas, and MNSEP showed giant cortical SEP. Brain biopsy revealed intraneuronal accumulation of granular osmiophilic deposits (GROD), which is characteristic of electromicroscopic findings of neuronal ceroid lipofuscinosis (NCL). We report biopsy-proven adult NCL, which is one of the rare neurodegenerative diseases. (J Korean Neurol Assoc 19(1):45~48, 2001

Juvenile neuronal ceroid lipofuscinosis.

A case of juvenile neuronal ceroid lipofuscinosis (JNCL) diagnosed on the basis of clinical features, electrophysiologic studies and skin electron microscopy is reported. JNCL was suspected on the basis of characteristic symptoms including progressive loss of vision, seizures, mental retardation and motor disabilities. Diagnosis was confirmed by neurophysiological and biopsy studies. The disease is caused by 23 different mutations in a gene recently isolated on chromosome 16 p11.2-12.1. Although universally fatal, characterisation of mutations can help in prenatal diagnosis in future pregnancies.