Overview of the New EFNS’ Guidelines on Molecular Diagnosis of Neurological Disorders are rare17,18
and have mostly been found in cases with a strong dominant family history and a high prevalence of dementia, but SNCA-duplications can cause late-onset typical PD. In Europeans, mutations in the LRRK2 gene are a much more common cause of dominant PD, and thus molecular testing for LRRK2 is recommended in familial cases with dominant inheritance.19,20
Testing for the LRRK2
Testing for mutations in recessive PD-genes (parkin, PINK1, DJ-1) is recommended in families suggestive of recessive inheritance (affected sibling pairs) or sporadic patients with very early onset <35 years22
G2019S mutation is recommended in familial and also sporadic patients in specific populations, e.g. in the Ashkenazim or North African Arabs.21
(see Table 1).
Dystonia and Other Movement Disorders No genetic tests can be recommended in the more common focal dystonias, and molecular diagnosis of this phenotype is still restricted to a relatively small proportion with a clearly defined familial disease.23
The major cause of early-onset generalised dystonia is a deletion of the trinucleotide GAG (encoding glutamic acid) in the gene for torsinA on chromosome 9q34 (DYT1).24
More than 50% of
patients with this phenotype have this mutation. Due to the reduced penetrance of the GAG-deletion, DYT1-mutation carriers often have a negative family history. Molecular testing for this GAG-deletion is recommended (see Table 1) in patients with early- (<26 years) and limb-onset generalised dystonia, regardless of their family history.25
Early-onset generalised dystonia with a clear response to levodopa (levodopa-responsive dystonia) is most commonly found to be caused by point mutations or exon deletions in the gene encoding GTP-cyclohydrolase-1 (GCH1).26
Spastic Paraplegia
The hereditary spastic paraplegias (HSPs) are characterised by slowly progressive pyramidal tract dysfunction occurring in either ‘pure’ or ‘complicated’ forms, the latter being associated with various other neurologic signs and symptoms.37
To date, about 40 genetically Testing for GCH1-mutations including
gene dosage studies is recommended in these patients. In patients with a typical clinical picture and a family history suggestive of myoclonus-dystonia syndrome, sequencing and gene dosage studies of the SGCE-gene27
gene can confirm a diagnosis of Wilson disease for family counselling purposes.28
However, blood and urine chemistry, particularly copper excretion in urine and serum coeruloplasmin levels, is still the diagnostic method of choice in the majority of Wilson cases.
Ataxias
In patients with an adult onset of slowly progressive ataxia and a family history compatible with autosomal dominant inheritance, genetic testing should include SCA1, 2, 3, 6, 7 and 17, which represent the majority of the presently identified genotypes for one of the spinocerebellar ataxias in Europe.29–32
Among those, priorities
should be chosen according to associated clinical features: a pure cerebellar syndrome occurs in SCA6, while SCA1, 2 and 3 patients show variable involvement of the extrapyramidal, pyramidal and peripheral nervous system (see Table 1). Cases with SCA7 are typically distinguished by retinal degeneration. In male patients with late-onset ataxia, particularly if combined with a mixed tremor, extrapyramidal symptoms and mild cognitive deterioration, testing for the fragile X-tremor-ataxia syndrome (FXTAS), which is caused by a pre-mutation in the FMR1 gene (a CGG-trinucleotide-repeat, expanded to a size of 55 to 200 repeats), is recommended. A multitude of different recessive syndromes with progressive ataxia as the clinical core symptom have been recognised.33
Most cases have
onset in childhood or early adulthood, but late-onset cases are increasingly recognised and should be considered in the differential diagnosis of any ataxic patient. In cases presenting with a
EUROPEAN NEUROLOGICAL REVIEW
distinct forms are recognised, and in almost half of them the genes have been identified. There are about as many autosomal dominant (AD) as recessive (AR) forms, in addition to at least 3 X-linked HSPs. Most of the AD-HSPs present clinically as pure HSP, while most of the AR–HSPs are complicated forms.
are recommended. Sequencing of the ATP7B
Patients with pure HSP and a family history of spastic paraparesis should be tested for point mutations in the SPAST gene (SPG4), which account for almost 50% of these cases (see Table 1).38
If direct
sequencing of the gene is negative, a multiplex ligation-dependent probe amplification assay (MLPA) should be applied to identify genomic rearrangements. As a third step, sequencing of atlastin (SPG3)39
combination of early-onset ataxia, peripheral sensory neuropathy and absence of marked cerebellar atrophy on magnetic resonance imaging (MRI), genetic tests for the most common form of recessive ataxia, Friedreich’s ataxia (FRDA) is recommended.34
The disease is
caused by an easily detectable trinucleotide repeat (GAA) in intron 1 of the FRDA gene.33
Genetic testing can be helpful in several other
rare recessive forms of ataxia. Molecular testing for ataxia telangiectasia (ATM),35 AOA2)36
ataxia with oculomotor apraxia (AOA1 and
is recommended when guided by reduced levels of albumin or increased levels of cholesterol (in AOA) or elevated alpha-fetoprotein (in ATM), even in the absence of conspicuous clinical features. Ataxia with vitamin E deficiency (AVED) can usually be diagnosed reliably by measuring vitamin E levels in serum. However, molecular diagnosis can be helpful for early detection in siblings of patients with an established diagnosis, and thus may help to institute early nutritional therapy. In the rare patient with clearly distinct attacks of ataxia and vertigo, a form of the episodic ataxias can be suspected. Genetic testing for EA1 and EA2 is available in some specialised laboratories.
In putatively recessive cases, molecular testing first for SPG11 and second for SPG15 is recommended in patients with a thin corpus callosum. SPG7 should be tested, especially when cerebellar features are present. For other recessive and X-linked forms of HSP no general recommendation can be given. Subjects with sporadic progressive spastic paraparesis should be tested for SPG4 mutations by MLPA after careful exclusion of other causes of spasticity. In negative cases, sequencing of SPG7 can be proposed.
Dementia
Inherited degenerative dementias occur in variable proportion of the cohorts, most often as autosomal-dominant disorders and have similar phenotypes to the sporadic disease. Particular attention needs to be given to adequate genetic counselling and consenting from the patient and/or family caregiver prior to any attempt of molecular genetic diagnosis in dementing disorders.41
In most instances, 13
in subjects with a pure form and onset under 20 years is recommended. All other forms are very rare. Sequencing of REEP1 and KIF5A can be considered in remaining mutation-negative dominant families, the latter particularly when a neuropathy is present. If the pedigree analysis suggests an X-linked form, testing for mutations in L1-CAM and PLP (SPG 1 and SPG2) should be proposed in early onset complex forms of HSP with white-matter changes on MRI.40
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