Infantile Neuroaxonal Dystrophy

[Seitelberger syndrome. Includes: Atypical Infantile Neuroaxonal Dystrophy, Classic Infantile Neuroaxonal Dystrophy]

Clinical Diagnosis

Until 2006, when the PLA2G6 gene was identified as causative [Morgan et al 2006], the diagnosis of infantile neuroaxonal dystrophy (INAD) was established by clinical and pathologic findings alone. Currently, molecular genetic testing helps confirm the diagnosis and in many cases eliminates the need for tissue biopsy.

Note: Assessment of a large cohort of individuals with INAD clarified the clinical findings of classic INAD. Screening of additional individuals with idiopathic neurodegeneration with brain iron accumulation (NBIA) for PLA2G6 mutations identified individuals with atypical NAD [Gregory et al 2008, Kurian et al 2008].

Testing

Tissue biopsy. Before the availability of molecular genetic testing, identification of dystrophic axons on electron microscopic examination of nerve ultrastructure in a tissue biopsy of conjunctiva, skin, muscle, sural nerve, or rectum was the finding necessary to establish the diagnosis of INAD. Because axonal spheroids accumulate with age and may not be evident in all tissues, individuals with INAD may require multiple biopsies over time before axonal spheroids are identified. Therefore, a negative biopsy cannot rule out INAD; a positive biopsy is considered diagnostic.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. PLA2G6 is the only gene known to be associated with INAD and atypical NAD.

Other loci. Linkage data support the presence of at least one additional INAD locus [Morgan et al 2006].

Clinical testing

• Sequence analysis. Sequence analysis of the coding region and splice sites of PLA2G6 is thought to identify approximately 85% of mutations. For the entire population of individuals positive for PLA2G6 mutations, approximately 10% have only one allele identified [NBIA International Mutation Database, unpublished data].

• Deletion/duplication testing. Large intragenic deletions may account for some of the mutations not detected by sequence analysis. This possibility is based on the presence of individuals in whom only one mutation is identifiable by mutation scanning.

Table1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Infantile Neuroaxonal Dystrophy

Gene Symbol	Proportion of INAD Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
PLA2G6	~95%	Sequence analysis	Sequence variants	85%	Clinical
		Deletion/duplication testing 1	Exonic or whole-gene deletions	Unknown

1. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), and array CGH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

The steps to confirm the diagnosis in a proband have been altered by the advent of molecular genetic testing.

When the clinician suspects a diagnosis of INAD, an ophthalmologic examination and brain MRI are recommended first because optic atrophy and cerebellar atrophy are strong clinical features:

• If suspicion remains high, molecular genetic testing of PLA2G6 is recommended as the next step instead of an invasive biopsy.

• If no PLA2G6 mutations are found but the evolving phenotype remains most consistent with INAD, a biopsy to assess for axonal spheroids could be considered. Preferred tissues are, in order: conjunctiva, skin, rectum, other peripheral nerve.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

Though still only speculative, mutations in PLA2G6 may underlie Schindler disease as well. This may explain the discordance between the clinical and biochemical phenotypes observed in Schindler disease, which is categorized as a neuroaxonal dystrophy. Schindler disease was originally reported in sibs with early-onset, rapidly progressive psychomotor regression, evidence of axonal spheroids, and deficiency of α-N-acetylgalactosaminidase (α-NAGA) [Schindler et al 1989]. Alpha-NAGA deficiency underlies the oligosacchariduria found in Schindler disease, but its causal role in the neurologic phenotype has been questioned because other persons with α-NAGA deficiency have a spectrum of clinical findings ranging from angiokeratoma to no abnormalities [Keulemans et al 1996, Bakker et al 2001].

The authors have proposed that mutations in PLA2G6 account for the early-onset neurodegenerative phenotype that occurs in a subset of individuals with Schindler disease based on their common clinical and pathologic features, their interrelatedness, and the proximity of PLA2G6 to NAGA on chromosome 22 [Westaway et al 2007]. Molecular genetic testing of samples from the original sibs diagnosed with Schindler disease should resolve this question; such samples have not been available.

Natural History

Classic INAD. Onset of classic disease usually occurs between ages six months and three years. Disease presents with psychomotor delay, delayed walking, or gait disturbance. Eventually, psychomotor regression is evident with loss of previously acquired milestones.

Truncal hypotonia, observed early in disease course, is eventually replaced by spastic tetraparesis, a characteristic of progression specific to infantile neuroaxonal dystrophy (INAD). Symmetric pyramidal tract signs are also frequently seen.

Visual signs and symptoms are common. Strabismus and nystagmus are early features of the disease. Later optic atrophy occurs in most cases. Optic atrophy may be observed early as optic nerve pallor; thin optic chiasm and tracts have also been reported on brain MRI [Farina et al 1999].

Seizures occur in a minority of individuals as a later symptom [Nardocci et al 1999].

The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications.

Atypical NAD. Whereas the features of classic INAD are relatively homogeneous, atypical disease is quite varied.

In general, onset in atypical cases is in early childhood but can be as late as the late teens. In a series of 13 individuals, four had onset by age three years but a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years [Nardocci et al 1999].

The presenting signs and symptoms may be similar to classic INAD, including gait instability or ataxia. Others may present with speech delay and autistic features, which may remain as the only evidence of disease for a year or more given the slow progression of atypical disease compared to classic disease [Gregory et al 2008].

Although tetraparesis (i.e., spasticity) is present late in the disease, it is not necessarily preceded by early truncal hypotonia. In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical cases. Eye findings are similar to classic INAD. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [Gregory et al 2008].

Aypical cases are rare, and the life span is not known; however, it is expected to be longer than that observed in classic disease.

Genotype-Phenotype Correlations

Genotype correlates with phenotype to a limited extent:

• All individuals with two null alleles of PLA2G6 had classic INAD.

• The less severe atypical NAD phenotype is caused exclusively by compound heterozygosity for missense mutations.

Nomenclature

Outdated terms. Seitelberger [1952] first described this condition, which was originally named Seitelberger disease.

Karak syndrome was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [Mubaidin et al 2003]. Morgan et al (2006) identified mutations in PLA2G6 in individuals with Karak syndrome, which is now included in the phenotypic spectrum of INAD and is no longer considered to be a clinically distinct entity.

Current nomenclature. In addition to INAD, later-onset variants have been called late infantile, juvenile, or atypical neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (NBIA).

The authors propose the following usage:

• Classic INAD for early-onset, rapidly progressive disease

• Atypical NAD for later childhood-onset disease with slower progression and extrapyramidal findings (dystonia, dysarthria). The atypical NAD phenotype is expected to include a broad range of presentations.

Prevalence

Disease prevalence is not established; it is estimated at approximately 1:1,000,000.

Infantile Neuroaxonal Dystrophy (INAD)

Early diagnosis of infantile neuroaxonal dystrophy (INAD) is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions.

The degree of weakness early in the disease course may initially direct the clinician toward a myopathy or spinal muscular atrophy.

Cerebellar atrophy can be detected by brain MRI before age two years in some children [Farina et al 1999]. The differential diagnosis for childhood cerebellar atrophy includes infantile neuronal ceroid-lipofuscinosis (Santavuori-Haltia), ataxia-telangectasia, and hereditary ataxia; however, cerebellar atrophy usually presents later for these disorders.

An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T2-weighted MRI. For this reason, conditions included in the NBIA category should also be considered in the differential diagnosis of INAD. Individuals with INAD have not been found to have an eye-of-the-tiger sign, which specifically correlates with pantothenate kinase-associated neurodegeneration (PKAN) [Hayflick et al 2003].

Since the identification of PLA2G6 mutations as causative of INAD, the need for invasive nerve biopsy to aid in diagnosis has decreased. While the presence of axonal spheroids in peripheral tissues remains specific to INAD, spheroids are found in brain in a few other conditions, including PKAN, idiopathic NBIA, infantile GM2 gangliosidosis (see Hexosaminidase A Deficiency), Niemann-Pick disease type C, and Menkes disease (see ATP7A-Related Copper Transport Disorders).

Atypical Neuroaxonal Dystrophy (NAD)

Initial speech delay and limited social interaction may be consistent with autism (see Autism Overview).

Spasticity, dystonia, and dysarthria, findings similar to those of other forms of NBIA, eventually predominate; high brain iron in the globus pallidus and substantia nigra has been observed in nearly all cases, although ascertainment is likely to be biased [Gregory et al 2008]. Therefore, idiopathic NBIA should also be considered in the differential diagnosis of atypical NAD. PKAN may present with similar features.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with infantile neuroaxonal dystrophy (INAD), the following evaluations are recommended:

• Thorough ophthalmologic examination (if not performed during the diagnostic evaluation) to assess for optic atrophy

• EEG for the possibility of unrecognized seizure activity

Note: The extent of disease is often well-characterized by the time of diagnosis, since the diagnostic work-up frequently includes neurophysiologic studies (EEG, EMG, electroretinogram (ERG), and/or visual evoked potentials) and brain MRI.

Treatment of Manifestations

The following treatments for INAD are palliative:

• Pharmacologic treatment of spasticity and seizures

• Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (see Dystonia Overview)

• Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms

• Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications

• Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions

• Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia

Prevention of Secondary Complications

A rehabilitation program including physical therapy and orthopedic management should be initiated early in the disease course to prevent contractures when the individual is permanently nonambulatory.

Surveillance

Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Because a portion of individuals with INAD have high brain iron and this disorder falls into the category of NBIA, the option of chelation therapy is sometimes raised. Anecdotal evidence suggests that current chelation therapies are unable to reduce brain iron levels, and this type of therapy is not currently recommended.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Infantile neuroaxonal dystrophy (INAD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with INAD have not been known to reproduce.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known. The following situations may arise when carrier detection is pursued by at-risk individuals and their reproductive partners:

• Two disease-causing PLA2G6 mutations are identified in the proband. In this case, the at-risk family member can be offered testing for the family-specific mutations to clarify his/her carrier status.

• Only one PLA2G6 mutation is identified in the proband. Molecular genetic testing will be informative for relatives related to the parent with the identifiable mutation. Molecular genetic testing will not be informative for relatives related to the carrier parent in whom no mutation has been identified.

• Neither disease-causing mutation is identified in the proband. Molecular genetic testing of relatives will not be informative.

• The proband is deceased, and no DNA-based testing was performed. It is appropriate to attempt to obtain any available tissue samples for DNA extraction for PLA2G6 molecular genetic testing. If DNA cannot be obtained, it is appropriate to test at-risk family members following genetic counseling in which the limitations of testing are explained. For those family members in whom a PLA2G6 mutation is not identified, a revised carrier risk can be calculated.

• A person has a reproductive partner who is a known carrier or is at risk of being a carrier. The reproductive partners of carriers or those at risk of being carriers can be offered molecular genetic testing with the understanding that a negative result can reduce but does not eliminate their risk of being a carrier.

Related Genetic Counseling Issues

Testing of at-risk sibs. The proband may have younger or similarly-aged sibs who could be affected. Although early diagnosis is not likely to significantly reduce morbidity or mortality, the family may desire testing of the at-risk sibs:

• If both PLA2G6 mutations have been identified in the proband, the sibs may be tested to determine if they have inherited both PLA2G6 disease-causing mutations.

• If the PLA2G6 mutations have not been identified in the proband, a plan for assessing at-risk sibs should be designed based on the primary findings in the proband and the established clinical criteria for INAD. Evaluations are likely to include brain MRI, ophthalmologic assessment, and possibly biopsy for histologic examination of peripheral nerves (see Diagnosis).
  
  Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without PLA2G6 mutations. A normal MRI and absence of other symptoms (including regression) in a sib who is older than the affected sibling was when cerebellar atrophy and/or other symptoms were present is reassuring.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by molecular genetic testing of DNA extracted from fetal cells obtained by amniocentesis at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the PLA2G6 gene must be identified in the affected sib or both parents before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

The PLA2G6 gene encodes iPLA₂-VIA, a calcium-independent phospholipase. This family of phospholipase A₂ enzymes catalyzes the hydrolysis of glycerophospholipids, generating a free fatty acid (usually arachidonic acid) and a lysophospholipid. The encoded protein has proposed roles in phospholipid remodeling, arachidonic acid release, leukotriene and prostaglandin synthesis, and apoptosis [Balsinde & Balboa 2005]. The iPLA₂ enzymes play a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids [Baburina & Jackowski 1999]. Defects in iPLA₂-VIA could lead to a relative abundance of membrane phospholipids or skewing of the proportions of specific species and secondary structural abnormalities, which may contribute to the axonal pathology observed in INAD [Morgan et al 2006].

Normal allelic variants. The PLA2G6 gene has 17 exons that are alternatively spliced to create transcripts encoding multiple protein isoforms [Larsson et al 1998]. No commonly occurring gene polymorphisms have been identified to date.

Pathologic allelic variants. The original report of disease-causing mutations in PLA2G6 described 44 unique mutations, including 32 missense, five deletions leading to a frameshift, three nonsense, two leading to amino-acid deletions without a frameshift, one splice site, and one large deletion [Morgan et al 2006]. Some mutations have been identified in multiple families reported to be unrelated, although several share ethnic backgrounds [NBIA International Mutation Database, unpublished data].

Normal gene product. PLA2G6 encodes iPLA₂-VIA, one of several calcium-independent phospholipases. The protein is active as a tetramer. PLA2G6 transcript variants encode multiple isoforms [Larsson et al 1998].

Abnormal gene product. The two enzymatically active forms of the protein are predicted to be affected by all of the mutations reported to date [Morgan et al 2006]. A subset of mutations would also alter the shorter enzymatically inactive isoforms, which seem to act as dominant-negative inhibitors when incorporated in the tetramer [Larsson et al 1998, Balsinde & Balboa 2005].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Acknowledgments

This work was supported in part by grants from the National Institute of Child Health and Human Development, the National Eye Institute, L'Association Internationale de Dystrophie Neuro Axonale Infantile, and the NBIA Disorders Association. This work was made possible by support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

Revision History

• 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically

• 19 June 2008 (me) Review posted live

• 14 June 2007 (ag) Original submission