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Arquivos de Medicina

versão On-line ISSN 2183-2447

Arq Med vol.24 no.3 Porto jun. 2010



Prenatal Diagnosis of Infantile Neuroaxonal Dystrophy

Diagnóstico Prenatal de Distrofia Neuroaxonal

Fátima Pinto*, Carla Pina*, Maria Céu Rodrigues*, Inês Carrilho*, Joaquim Saraiva*, Maria José Mendes*, Joana Santos*, Márcia Martins*


*Centro de Diagnóstico Pré-Natal, Maternidade de Júlio Dinis e Serviço de Neuropediatria,Centro Hospitalar do Porto





Infantile Neuroaxonal Dystrophy (INAD1, MIM # 256600), is a rare autossomal recessive neurodegenerative disorder. The clinical picture is characterized by psychomotor regression and hypotonia, which progresses to spastic tetraplegia, visual impairment and dementia. Onset is within the first 2 years of life and death usually happens before the age of 10. In 2006, Morgan et al described that mutations in PLA2G6 gene localized in chromosome 22 (22q13), caused INAD1. Evidence showed that a large proportion of patients with infantile neuroaxonal dystrophy have a mutation in the PLA2G6 gene.

A 36-years-old pregnant woman presented for obstetric follow up. It was the second pregnancy of this healthy, nonconsanguineous couple. Their 7 year-old daughter was affected with Infantile Neuroaxonal Dystrophy. Molecular testing was done in the child and, as a causal mutation was detected, it was possible to offer a specific prenatal diagnosis.

The molecular study of PLA2G6 gene by amniocentesis showed the presence of a mutation in heterozygoty and the karyotype was normal for a female foetus. To our knowledge, this is the first molecular prenatal diagnosis of INAD1 in Portugal.

Key-words: neuroaxonal; dystrophy; PLA2G6.



A Distrofia Neuroaxonal Infantil (DNAI) é um distúrbio neurodegenerativo grave, com hereditariedade autossómica recessiva. O quadro clínico caracteriza-se por regressão psicomotora e hipotonia, com progressão rápida para tetraplegia espástica, cegueira e demência. A morte sobrevém geralmente antes dos 10 anos de idade. Recentemente demonstrou-se que mutações no gene PLA2G6, localizado no cromossoma 22 (22q13.1), são responsáveis pela patologia e que a grande maioria destes doentes apresenta mutações no gene PLA2G6.

Apresentamos o caso clínico de uma grávida de 36 anos, IIGIP, casal saudável, não consanguíneo, com uma filha de 7 anos de idade com diagnóstico de DNAI. Foi efectuado o estudo molecular na criança doente que confirmou o diagnóstico e possibilitou o diagnóstico pré-natal específico na presente gestação. No liquido amniótico o estudo molecular do gene PLA2G6 revelou a presença de uma mutação em heterozigotia; o cariótipo foi normal para um feto do sexo feminino. Tanto quanto sabemos, este é o primeiro diagnóstico pré-natal de exclusão de DNAI em Portugal.

Palavras-chave: neuroaxonal; distrofia; PLA2G6



Infantile Neuroaxonal Dystrophy (INAD1; # 256600) is a severe and rapidly progressive neurodegenerative disease with an autossomal recessive inheritance. INAD comprises a classic and an atypical form. The classic form begins before age three with hypotonia, progressive psychomotor delay and symmetric pyramidal tract signs (strabismus, nystagmus and optic atrophy). The atypical form begins in early childhood with gait instability, ataxia, speech delay, autistic features with neurologic deterioration and extrapyramidal findings; neuropsychiatric disturbances including poor attention, hyperactivity and emotional lability are also commun (1,2,3). Death usually occur before age of 10 (2). The hallmark of the disease is widespread focal swelling and degeneration of axons with scattered spheroid bodies in both central and peripheral nervous system (2,4). Cerebellar atrophy and signal hiperintensity in the cerebellar cortex on T2-weigthed MRI images are characteristic but not pathognomonic (3,5). The differential diagnosis for childhood cerebellar atrophy includes neuronal ceroidlipofuscinosis (Santavuori-haltia), ataxia-telangiectasia, and hereditary ataxia (1). Spheroids are found in brain in other conditions, including PKAN, idiopatic NBIA, infantile GM2 gangliosidosis, Niemann-Pick disease type C, and Menkes disease (1). Fast rhythms on EEG were observed in all patients (6).

The frequency of INAD is unkown. Currently no effective treatment isavailable.Therapeuticapproach involves treatment of manifestations for spasticity and seizures, control of secretions, prevention of aspiration pneumonia by feeding modifications, psychiatric support, prevention of secondary complications with physiotherapy and periodic assessment of vision and hearing (1).

The disease gene, PLA2G6 - the gene encoding phospholipase A2 group VI, was mapped in 2006 by Morgan et al to a 1.17-Mb locus on chromosome 22q13.1 (7).



We present a 36-years-old pregnant woman, II Gesta I Para, healthy non consanguineous couple. Before this pregnancy they had preconceptional counselling as their 7years-olddaughter, was affected by Infantile Neuroaxonal Dystrophy. At that time, the molecular basis of the disease remained unkown. A few months later, when she got pregnant, we confirmed the recent possibility of molecular testing. The results showed composed heterozigoty for 2 pathological mutations in the affected child (c.1442T>A and c.2370T>G. Based on this molecular characterization, it was possible to offer a specific prenatal diagnosis and an amniocentesis was performed.



The karyotype was normal for a female foetus and molecular study of PLA2G6 gene showed the presence of the mutation c1442T>A in heterozygoty, which was compatible with a status of a healthy carrier. Pregnancy was uneventful.

At 39th weeks, due to oligoamnios, labour was induced with a vaginal delivery of a healthy girl (2990 g, 48 cm and 9/10 Apgar score).



Authors emphasize the role of preconceptional counselling in identification and orientation of couples with genetic risk. Diagnosis of familiar diseases allows a correct genetic counselling and in many cases the possibility of a specific prenatal diagnosis in future pregnancies, allowing couples informed decisions. Molecular prenatal diagnosis is the best approach if a mutation within the family is identified in a timely manner.

Authors highlight the need of a continuous actualization, involving each member of a prenatal diagnosis team, taking in account the fast evolution of Genetics field.

To our knowledge this case documents the first molecular prenatal diagnosis INAD in Portugal.

The molecular analysis of the affected sister was done at the Medical Institute of Genetics of OPorto with probes provided by the laboratory Molecular & Medical Genetics (Dr Susan Hayflick) -Oregon Health & Science University -Portland – USA.



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2 -Blanco-Barca MO, Eiris-Puñal J, Peña-Guitian J, Fernández-Bustillo JM, Pintos-Martínez E, Castro-Gago M. Mixed hypotonia, neurological regression and atrophy of the cerebellum: manifestations that suggest infantile neuroaxonal dystrophy. Rev Neurol 2003;37:25-8.         [ Links ]

3 -Biancheri R, Rossi A, Alpigiani G, et al. Cerebellar atrophy without cerebellar cortex hyperintensity in infantile neuroaxonal dystrophy (INAD) due to PLA2G6 mutation. Eur J Paediatr Neurol 2007;11:175-7.         [ Links ]

4 -Khateeb S, Flusser H, Ofir R, et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet 2006;79:942-8.         [ Links ]

5 -Mutlu H, Sildiroglu HO, Sonmez G, Ozturk E, Kizilkaya E. Neuroaxonal dystrophy: MR imaging, proton MR spectroscopy, and diffusion MR imaging findings. J Neuroradiol 2006;33:207-8.         [ Links ]

6 -Carrilho I,SantosM,GuimarãesA,etal.Infantile neuroaxonal dystrophy: What´s most important for the diagnosis. Eur J Paediat Neurol 2008;12:495-500.         [ Links ]

7 -Morgan NV, Westaway SK, Morton JE, et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 2006;38:752-4.         [ Links ]



Dr.ª Fátima Pinto

Serviço de Obstetrícia - Centro de Diagóstico Prénatal da Maternidade de Júlio Dinis, Centro Hospitalar do Porto Maternidade de Júlio Dinis Largo da Maternidade, 4050-371 Porto. E-mail:

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