7 Genetic Syndromes ADENYLOSUCCINATE LYASE DEFICIENCY A disorder of purine synthesis, adenylosuccinate lyase deficiency is a rare condition, with only about 40 published cases. It presents in early life with mental retardation and seizures. Although no specific diagnostic criteria have been proposed for the clinical syndrome, Table 1 summarizes clinical findings in 20 patients and may be useful as a guide in suspecting the diagnosis. ALEXANDER’S DISEASE Alexander’s disease is a rare genetic disease, presenting primarily in childhood. The genetic basis of Alexander’s disease involves mutations in the glial fibrillar acidic protein (GFAP) gene. Individuals with Alexander’s disease may present as infants, children, or rarely, as adults. Infants and children typically present with seizures, megalencephaly, developmental delay, and spasticity. Particularly in older patients, there may be bulbar or pseudobulbar symptoms, and spasticity, especially of the legs. The disease is progressive, with most patients dying within 10 years of onset. Until recently, the diagnosis has been pathological, with demonstration of Rosenthal fibers on brain biopsy. Genetic testing combined with clinical course and neuroimaging may be sufficient for diagno- sis. Other similar clinical syndromes may be seen with mutations in other genes, and differential diag- nosis is that of other leukoencephalopathies. In the study presented in Table 2, patients were included if they fulfilled the following minimum criteria: (1) magnetic resonance imaging findings of white matter changes with preferential involvement of the frontal regions of the brain; (2) normal karyotype; (3) normal metabolic screening; and (4) no family history of any leukoencephalopathy. ANGELMAN SYNDROME These criteria are applicable for the three major types of Angelman syndrome: molecular deletions involving the critical region (deletion-positive), uniparental disomy, and nondeletion/nonuniparental disomy. Angelman syndrome is currently clinically diagnosed and can be confirmed by laboratory testing in about 80% of cases. Individuals whose developmental history conforms to that described in Table 3, and who have all of the clinical findings of groups A and B in Table 4 should have a chromosome study, as well as molecular analysis by fluorescence in situ hybridization, polymorphism analysis, or methy- lation testing to look for alterations in chromosome region 15q11–q13. A positive genetic test (Table 5) may confirm the diagnosis, but a normal result does not exclude the diagnosis. In individuals with fewer clinical findings, a positive genetic test is presumptive evidence for Angelman syndrome. The judgment of the clinician is crucial when genetic testing is negative and clinical findings suggest the syndromic diagnosis. For individuals with no deletion or uniparental disomy, the clinician should be reasonably certain that the clinical findings in Tables 3 and 4 are present if the diagnosis of Angelman syndrome is still considered. From: Current Clinical Neurology: Diagnostic Criteria in Neurology Edited by: A. J. Lerner © Humana Press Inc., Totowa, NJ 83 Table 1 Clinical Findings in 20 Patients With Adenylosuccinate Lyase Deficiency S-Ado/ Seizure Psychomotor Autistic SAICAR, Author Sex onset EEG retardation features Others CT/MRI md/mL Outcome Jaeken et al., 1984 F — Normal Yes No eye Axial Cerebellar — Severe mental contact hypotonia, hypoplasia retardation growth retardation M 7 years Generalized Yes No eye Axial Cerebellar — Seizure abnormalities contact, hypotonia, hypoplasia, controlled by no language growth cortical CBZ retardation, atrophy muscular wasting F 2 years Diffuse slowing Yes No eye Growth Cerebellar — Seizure 8 contact, retardation, hypoplasia controlled by 4 no language muscular CBZ wasting Jaeken et al., 1988 M NR Abnormal Yes — — — — Died (13 years) F NR Abnormal Yes No eye Unvoluntary Cerebellar — Mild mental contact movements of hypoplasia retardation extremities, peripheral hypertonicity F 1 week Hypsarrhythmia Yes No eye Peripheral Cortical/ — Severe mental contact, hypertonicity cerebellar retardation, stereotypies atrophy intractable epilepsy M — Normal Yes No eye Strabismus, Normal — Severe mental contact, growth retardation stereotypies retardation F NR Diffuse slowing Yes No eye Growth Cerebral 4–5 Mild mental contact, retardation atrophy retardation, hypoacusia intractable epilepsy Jaeken et al., 1992 F 5 years Generalized Yes Aggressivity, — Slight cerebral 1.77 Mild mental abnormalities stereotypies atrophy retardation Salerno and Crifo F 7 months Focal/generalized Yes No language, Ataxia, — 1.2 Severe mental 1994 abnormalities stereotypies strabismus, retardation, muscular intractable wasting, epilepsy hyperactivity, Apraxia, growth retardation Sebesta et al., M NR Abnormal Yes — Hypotonia, Abnormal —Mild mental 1997 hyperactivity retardation FNRAbnormal Yes — Hypotonia, Abnormal —Mild mental hyperactivity retardation F 1 month Abnormal Yes — — Abnormal — Severe mental retardation F NR Abnormal Yes — — Abnormal — Died (15 years) M 1 month Abnormal Yes — — Abnormal — Severe mental retardation Maaswinkel-Mooij F 9 weeks HypsarrhythmiaYes— Axial Lack of 1.02 Severe mental 8 5 et al., 1997 hypotonia, myelinization retardation, peripheral intractable hypertoniaepilepsy Valik et al., 1997 F — Normal Yes — Muscular Increased T2 2.5–2.6 Severe mental hypotonia, signal in retardation fasciculations, semiovale strabismus center van den Bergh M2 days Burst Yes — Axial hypotonia— Died (7 months) et al., 1998 suppression Kohler et al., 1999 M 3 weeks Focal Yes No eye Muscular Slight 0.9 Severe mental abnormalities contact, hypotonia cerebral retardation, stereotypies atrophyseizure-free M3 days Status epilepticus, Yes — — Lack of 1.5 Died (6 months) burst suppression myelinization EEG, electroencephalography; CT, computerized tomography; MRI, magnetic resonance imaging; S-Ado, succinyladenosine; SAICA-R, succinylaminoimidazole carboxamide ribotide; NR, nonreferred; CBZ, carbamazepine. (Adapted with permission from Ciardo F, Costantino S, Curatolo P. Neurologic aspects of adenylosuccinate lyase deficiency. J Child Neurol 2001;16:301–308, and from BC Decker.) Table 2 Clinical and Molecular Findings in Patients With Alexander Disease Current status Mutation: Dementia exon/base Age at Bulbar and/or or Patient change/amino Initial onsetta/current pseudobulbar cognitive no./sex acid change presentation age ↑HCCb signs Seizures Spasticity deficits Other findings Infancy onset 1/F Exon 1 Seizures 3 months/ – Dysphagia, + + + Linear growth failure, 249C→G 3 years frequent vomiting, truncal hypotonia, no R79Gc or frequent language development choking episodes 2/M Exon 1 Seizures 6 months/ + Strabismus + – + Hypothyroidism 249C→T 5 years d 8 R79C 6 3/Me Exon 1 Seizures 18 months/ + Dysphagia, frequent + – + Born 3 weeks after 250G→A 9 yearsvomiting, or term; linear sebaceous R79Hd frequent choking nevi on scalp episodes; dysarthria or slurred speech 4/MMf Exon 1 Seizures 7 months/ + — ++ – 250G→A 2 years R79Hd 5/M Exon 4 Delayed motor 9 months/ + Dysarthria or – + – 729C→T development 4 years slurred speech R239Cd 6/M Exon 4 Failure to 12 months/ + Strabismus – – + 738T→G thrive; hypotonia 5 years Y242Dc 7/F Exon 6 Seizures 2 months/ + — + – N/A Born 10 days after 1131G→A 5 months term; noncongenital E373Kc truncal and appendicular hypotonia; poor weight gain, fussiness Juvenile onset 8/M Exon 1 Strabismus 9 years/ + Dysphagia, frequent + + + Stellate nevi 232T→G 15 years vomiting, or frequent M73R choking episodes; dysarthria or slurred speech; strabismus 9/M Exon 1 Excessive sleepiness, 7 years/ – Dysphagia, frequent – – + Linear growth failure 276C→T frequent vomiting 9 years vomiting, or frequent R88Cd choking episodes; dysarthria or slurred speech; strabismus 10e/M Exon 1 MRI changes N/Aa/4 years + — – – – Linear growth failure 276C→T observed during R88Cd evaluation for short stature 11/F Exon 8 Intractable 5 years/ – Dysphagia, frequent – – – Prone to episodes of 1260C→T vomiting 7 years vomiting, or frequent syncope after R416Wd choking episodes hyperventilation 12g/M Exon 8 MRI changes N/Aa/11 years – –– – – – Clumsiness and poor 8 → 7 1260C Tobserved after coordination R416Wd accidental eye (nonprogressive) injury 13h/F—Seizures 2 months/ + — + – + Frontal and parietal 10 yearsb white matter changes aNo age at onset is reported for Patients 10 and 12; evaluation for leukodystrophy was initiated only after incidental findings of white matter changes were discovered by MRI performed as part of examination for other conditions. bIncreased head circumference (↑HC) (megalencephaly) is positive (+) when the occipitofrontal circumference is >95th percentile for age. Patient 1 had HC trending at 2nd percentile, although her height and weight were <10th percentile as well; no language development is noted at current age (3 years). cParents’ DNA tested negative for the mutation. dThese mutations have previously been described: R79C, R79H, R88C, R239C, R416W. ePatient 3 was also homozygous for a 879G→A nucleotide change that results in a D295N amino acid change. This nucleotide change has previously been observed in 3% of healthy control subjects. In addition, this patient was also heterozygous for a silent 872G→A nucleotide change previously found in 9% of control subjects. Patients 10 and 13 were likewise heterozygous for these two nucleotide changes. Both of these nucleotide changes are found in exon 5. fPatient 4 was also heterozygous for a silent 110T→C nucleotide change