Alexander disease

General Information (adopted from Orphanet):

Synonyms, Signs: AxD
Number of Symptoms 75
OrphanetNr: 58
OMIM Id: 203450
ICD-10: E75.2
UMLs: C0270726
MeSH: D038261
MedDRA:
Snomed: 81854007

Prevalence, inheritance and age of onset:

Prevalence: 300 cases [Orphanet]
Inheritance: Autosomal dominant
[Orphanet]
Age of onset: All ages
[Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases: Abnormal eye movements
 -Rare eye disease
 -Rare genetic disease
Genetic neurodegenerative disease
 -Rare genetic disease
Leukodystrophy
 -Rare genetic disease
 -Rare neurologic disease
Rare neurodegenerative disease
 -Rare neurologic disease

Symptom Information: Sort by abundance 

1
(HPO:0011037) Decreased urine output Frequent [Orphanet] 47 / 7739
2
(HPO:0002839) Urinary bladder sphincter dysfunction Frequent [Orphanet] 34 / 7739
3
(HPO:0004481) Progressive macrocephaly 8 / 7739
4
(HPO:0002007) Frontal bossing Very frequent [Orphanet] 366 / 7739
5
(HPO:0010628) Facial palsy Frequent [Orphanet] 146 / 7739
6
(HPO:0001357) Plagiocephaly Frequent [Orphanet] 106 / 7739
7
(HPO:0000470) Short neck Occasional [Orphanet] 345 / 7739
8
(HPO:0002705) High, narrow palate Occasional [Orphanet] 308 / 7739
9
(HPO:0100729) Large face Very frequent [Orphanet] 19 / 7739
10
(HPO:0000508) Ptosis Frequent [Orphanet] 459 / 7739
11
(HPO:0000639) Nystagmus Frequent [Orphanet] 555 / 7739
12
(HPO:0000651) Diplopia Frequent [Orphanet] 37 / 7739
13
(HPO:0000496) Abnormality of eye movement Frequent [Orphanet] 79 / 7739
14
(HPO:0001347) Hyperreflexia Very frequent [Orphanet] 363 / 7739
15
(HPO:0002376) Developmental regression 74 / 7739
16
(HPO:0002270) Abnormality of the autonomic nervous system Occasional [Orphanet] 22 / 7739
17
(HPO:0001257) Spasticity 251 / 7739
18
(HPO:0007256) Abnormal pyramidal signs Very frequent [Orphanet] 116 / 7739
19
(HPO:0100716) Self-injurious behavior Occasional [Orphanet] 43 / 7739
20
(HPO:0002360) Sleep disturbance Very frequent [Orphanet] 113 / 7739
21
(HPO:0001288) Gait disturbance Frequent [Orphanet] 318 / 7739
22
(HPO:0100851) Abnormal emotion/affect behavior Frequent [Orphanet] 85 / 7739
23
(HPO:0004305) Involuntary movements Occasional [Orphanet] 50 / 7739
24
(HPO:0001251) Ataxia Common [HPO:probinson] 12975300 IBIS 413 / 7739
25
(HPO:0002922) Increased CSF protein 27 / 7739
26
(HPO:0002167) Neurological speech impairment Frequent [Orphanet] 308 / 7739
27
(HPO:0004374) Hemiplegia/hemiparesis Frequent [Orphanet] 158 / 7739
28
(HPO:0011442) Abnormality of central motor function Very frequent [Orphanet] 76 / 7739
29
(HPO:0002066) Gait ataxia Frequent [Orphanet] 327 / 7739
30
(HPO:0002383) Encephalitis Occasional [Orphanet] 41 / 7739
31
(HPO:0000712) Emotional lability Frequent [Orphanet] 44 / 7739
32
(HPO:0001250) Seizures Very frequent [Orphanet] 1245 / 7739
33
(HPO:0001337) Tremor Frequent [Orphanet] 200 / 7739
34
(HPO:0001276) Hypertonia Very frequent [Orphanet] 317 / 7739
35
(HPO:0100543) Cognitive impairment Occasional [Orphanet] 230 / 7739
36
(HPO:0002015) Dysphagia Frequent [Orphanet] 301 / 7739
37
(HPO:0002353) EEG abnormality Very frequent [Orphanet] 188 / 7739
38
(HPO:0000819) Diabetes mellitus Occasional [Orphanet] 131 / 7739
39
(HPO:0000821) Hypothyroidism Occasional [Orphanet] 141 / 7739
40
(HPO:0000826) Precocious puberty Occasional [Orphanet] 42 / 7739
41
(HPO:0002514) Cerebral calcification Frequent [Orphanet] 89 / 7739
42
(HPO:0002650) Scoliosis Very frequent [Orphanet] 705 / 7739
43
(HPO:0003307) Hyperlordosis Occasional [Orphanet] 122 / 7739
44
(HPO:0002808) Kyphosis Frequent [Orphanet] 289 / 7739
45
(HPO:0004349) Reduced bone mineral density Occasional [Orphanet] 165 / 7739
46
(HPO:0002017) Nausea and vomiting Very frequent [Orphanet] 134 / 7739
47
(HPO:0002019) Constipation Frequent [Orphanet] 194 / 7739
48
(HPO:0100247) Recurrent singultus Frequent [Orphanet] 7 / 7739
49
(HPO:0002607) Bowel incontinence Occasional [Orphanet] 33 / 7739
50
(HPO:0004325) Decreased body weight Very frequent [Orphanet] 492 / 7739
51
(HPO:0000995) Melanocytic nevus Occasional [Orphanet] 63 / 7739
52
(HPO:0000822) Hypertension Occasional [Orphanet] 224 / 7739
53
(HPO:0001695) Cardiac arrest Occasional [Orphanet] 87 / 7739
54
(HPO:0002615) Hypotension Frequent [Orphanet] 52 / 7739
55
(HPO:0002045) Hypothermia Frequent [Orphanet] 27 / 7739
56
(HPO:0002093) Respiratory insufficiency Occasional [Orphanet] 410 / 7739
57
(HPO:0002104) Apnea Frequent [Orphanet] 106 / 7739
58
(HPO:0001252) Muscular hypotonia Occasional [Orphanet] 990 / 7739
59
(HPO:0001324) Muscle weakness Occasional [Orphanet] 859 / 7739
60
(OMIM) Presence of Rosenthal fibers (cytoplasmic inclusions) in astrocytes 1 / 7739
61
(OMIM) Diffuse demyelination (increased signal intensity in T2-weighted images, especially frontal lobes) 1 / 7739
62
(HPO:0003593) Infantile onset 249 / 7739
63
(HPO:0001522) Death in infancy Occasional [Orphanet] 275 / 7739
64
(HPO:0002334) Abnormality of the cerebellar vermis Very frequent [Orphanet] 137 / 7739
65
(HPO:0012758) Neurodevelopmental delay Very frequent [Orphanet] 949 / 7739
66
(OMIM) Coarsened pattern of sulci and gyri 1 / 7739
67
(HPO:0007370) Aplasia/Hypoplasia of the corpus callosum Very frequent [Orphanet] 180 / 7739
68
(HPO:0000238) Hydrocephalus Occasional [Orphanet] 278 / 7739
69
(OMIM) Presence of glial fibrillary acidic proteins (GFAP) in astrocytes 1 / 7739
70
(OMIM) Presence of Rosenthal fibers (eosinophilic bodies near astrocyte filaments) 1 / 7739
71
(HPO:0007162) Diffuse demyelination of the cerebral white matter 3 / 7739
72
(HPO:0001355) Megalencephaly Very frequent [Orphanet] 39 / 7739
73
(HPO:0002483) Bulbar signs 9 / 7739
74
(HPO:0000006) Autosomal dominant inheritance 2518 / 7739
75
(HPO:0002410) Aqueductal stenosis Occasional [Orphanet] 19 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) In decreasing order of frequency, 3 forms of Alexander disease are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar ...
Diagnosis OMIM Van der Knaap et al. (2001) proposed specific MRI criteria for the diagnosis of Alexander disease: extensive, symmetric white matter abnormalities with frontal preponderance; periventricular signal changes; basal ganglia and thalamic signal changes; brainstem lesions; and contrast enhancement ...
Clinical Description OMIM This disorder, first described by Alexander (1949), is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia. The features are similar to those of Canavan disease (271900).

Gorospe et al. (2002) ...

Molecular genetics OMIM Mutations were found in the infantile form of Alexander disease by Brenner et al. (2001), in the juvenile form by Sawaishi et al. (2002), and in the adult form by Namekawa et al. (2002).

Brenner et ...

Diagnosis GeneReviews The clinical presentation of Alexander disease is nonspecific....
Clinical Description GeneReviews Alexander disease is a disorder of cortical white matter that predominantly affects infants and children and usually results in death within ten years after onset. Most individuals with Alexander disease present with nonspecific neurologic signs and symptoms....
Genotype-Phenotype Correlations GeneReviews The number of individuals confirmed as having mutations in GFAP is currently too small to make any conclusive genotype-phenotype correlations....
Differential Diagnosis GeneReviews The clinical presentation of Alexander disease often overlaps that of other neurologic disorders. It is usually considered in the differential diagnosis of infants who present with megalencephaly, developmental delay, spasticity, and seizures, or in older individuals who have a preponderance of brain stem signs and spasticity with or without megalencephaly or seizures. ...
Management GeneReviews To establish the extent of disease in an individual diagnosed with Alexander disease, the following evaluations are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....