Info

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.)

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

Patient

Mutation: exon/base change/amino acid change

Initial presentation

Age at onsets/current age

Bulbar and/or pseudobulbar signs Seizures Spasticity

Dementia or cognitive deficits

Other findings oo

Infancy onset

3/Me

4/Mf

Exon 1 249C^G R79Gc

Exon 1 249C^T R79Cd Exon 1 250G^A R79Hd

Exon 1 250G^A R79Hd Exon 4 729C^T R239Cd Exon 4 738T^G Y242Dc Exon 6 1131G^A E373Kc

Seizures

Seizures

Seizures

Seizures

Delayed motor development

Failure to thrive; hypotonia

Seizures

3 months/ 3 years

6 months/ 5 years

18 months/ 9 years

7 months/ 2 years

9 months/

4 years

12 months/

5 years

2 months/ 5 months

Dysphagia, frequent vomiting, or frequent choking episodes Strabismus

Dysphagia, frequent + vomiting, or frequent choking episodes; dysarthria or slurred speech

Dysarthria or slurred speech

Strabismus

Linear growth failure, truncal hypotonia, no language development

Hypothyroidism

Born 3 weeks after term; linear sebaceous nevi on scalp

Born 10 days after term; noncongenital truncal and appendicular hypotonia; poor weight gain, fussiness

Juvenile onset oo

10e/M

11/F

12S/M

Exon 1 232T^G M73R

Exon 1 276C^T R88Cd

Exon 1 276C^T R88Cd

Exon 8 1260C^T R416Wd Exon 8 1260C^T R416Wd

Strabismus

Excessive sleepiness, frequent vomiting

MRI changes observed during evaluation for short stature Intractable vomiting

MRI changes observed after accidental eye injury Seizures

9 years/ 15 years

7 years/ 9 years

N/A"/4 years

5 years/ 7 years

N/A"/11 years

2 months/ 10 years4

Dysphagia, frequent vomiting, or frequent choking episodes; dysarthria or slurred speech; strabismus Dysphagia, frequent vomiting, or frequent choking episodes; dysarthria or slurred speech; strabismus

Dysphagia, frequent vomiting, or frequent choking episodes

Stellate nevi

Linear growth failure

Linear growth failure

Prone to episodes of syncope after hyperventilation Clumsiness and poor coordination (nonprogressive)

Frontal and parietal white matter changes

"No 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.

increased head circumference (tHC) (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).

"Parents' DNA tested negative for the mutation.

^These mutations have previously been described: R79C, R79H, R88C, R239C, R416W.

"Patient 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.

•'Patient 4 was also heterozygous for a silent 110T^C nucleotide change in exon 1.

^Patient 12 also carried a 154C^T nucleotide change in exon 1 that is predicted to result in a P47L amino acid change. This nucleotide change has previously been described in another patient with Alexander disease who also had the 729C^T mutation.

^Patient 13 recently died in a drowning accident.

N/A, not applicable; MRI, magnetic resonance imaging.

(Reprinted with permission from Gorospe JR, Naidu S, Johnson AB, et al. Molecular findings in symptomatic and pre-symptomatic Alexander disease patients Neurology 2002;58:1494-1500.)

Angelman Syndrome: Developmental History and Laboratory Findings

1. Normal prenatal and birth history with normal head circumference.

2. Absence of major birth defects.

3. Developmental delay evident by 6-12 months of age.

4. Delayed but forward progression of development (no loss of skills).

5. Normal metabolic, hematological, and chemical laboratory profiles.

6. Structurally normal brain using magnetic resonance imaging or computerized tomography (may have mild cortical atrophy or dysmyelination).

These findings are useful as inclusion criteria, but deviations should not exclude diagnosis.

(Adapted with permission from Williams CA, Angelman H, Clayton-Smith J, et al. Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet. 1995;27;56:237—238, and from John Wiley and Sons.)

Table 4

Angelman Syndrome: Clinical Characteristics

A. Consistent (100%)

1. Developmental delay, functionally severe.

2. Speech impairment, none or minimal use of words; receptive and nonverbal communication skills higher than verbal ones.

3. Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs.

4. Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span.

B. Frequent (more than 80%)

1. Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2.

2. Seizures, onset usually younger than 3 years of age.

3. Abnormal electroencephalography, characteristic pattern with large amplitude slow spike waves (usually 2 to 3 per second), facilitated by eye closure.

1. Flat occiput.

2. Occipital groove.

3. Protruding tongue.

4. Tongue thrusting; suck/swallowing disorders.

5. Feeding problems during infancy.

6. Prognathia.

7. Wide mouth, widely spaced teeth.

8. Frequent drooling.

9. Excessive chewing/mouthing behaviors.

10. Strabismus.

11. Hypopigmented skin, light hair and eye color (compared with family), seen only in deletion cases.

12. Hyperactive lower limb deep tendon reflexes.

13. Uplifted, flexed arm position especially during ambulation.

14. Increased sensitivity to heat.

15. Sleep disturbance.

16. Attraction to/fascination with water.

Adapted with permission from Williams CA, Angelman H, Clayton-Smith J, et al. Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet 1995;56:237-238, and from John Wiley and Sons.)

In about 20% of individuals whose clinical presentation is characteristic of Angelman syndrome, genetic laboratory studies of chromosome 15 will be normal. These individuals are the "nondeletion/ nondisomy type." It is in the families of these individuals where familial recurrence is a possibility, whether methylation patterns are normal or abnormal. Although affected nondeletion/nondisomy siblings have

Table 5

Angelman Syndrome: Genetic Testing Abnormalities

1. High-resolution Giemsa (G)-banded chromosome study showing deletion of chromosome region 15q11—q13. Because of the possibility of false-positive and negative results from this study, G-banding should not be used as a stand-alone test but should be confirmed by fluorescence in situ hybridization (FISH), polymorphism, or methylation analysis.

2. Abnormal FISH indicating a deletion of cloned 15q11-q13 DNA sequences that are included in the Angelman syndrome deletion overlap region. Use of a pericentromeric FISH probe enhances ability to detect subtle translocation.

3. DNA polymorphism analysis showing absence of maternal alleles at 15q11-q13 loci, which may result either from maternal deletion or from paternal uniparental disomy

4. Characteristic DNA methylation pattern (i.e., paternal imprint only) of 15q11-q13 cloned DNA sequences using methylation-sensitive restriction endonucleases

5. An abnormal methylation pattern in individuals without 15q11-q13 deletion is not a stand-alone test for uniparental disomy.

Number of tests necessary and order of testing may vary. Chromosome study is necessary in all suspected cases to rule out chromosome rearrangements or other chromosome disorders.

(Adapted with permission from Williams CA, Angelman H, Clayton-Smith J, et al. Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation. Am J Med Genet 1995;56:237-238, and from John Wiley and Sons.)

been shown to share molecular haplotypes of the maternal 15 chromosome, there is currently no diagnostic test applicable to these individuals. Diagnosis in these situations remains clinical, although that may change as new testing and additional insight into the molecular cause of Angelman syndrome evolves.

The clinical diagnosis of Angelman syndrome usually is not suspected during the first year of life, but becomes a more frequent diagnostic consideration between 1 and 4 years of age. Angelman syndrome can be diagnosed in the first year (6-12 months) if the diagnosis is given due consideration. An abnormal electroencephalography may be the first sign for diagnostic evaluation. During infancy, other clinical disorders can mimic the features of Angelman syndrome. These include Rett's syndrome, nonspecific cerebral palsy, Lennox-Gastaut syndrome, static encephalopathy with mental retardation, infantile autism, and a-thalassemia X-linked mental retardation syndrome.

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