Information on the following diseases can be found in the Related Disorders section of this report:

• Angelman Syndrome
• Juberg-Marsidi Syndrome
• Mental Retardation, X-linked, Renpenning Type
• MASA Syndrome
• X-Linked Mental Retardation (General)

Allan-Herndon syndrome is primarily characterized by severe mental retardation, poor muscle tone (hypotonia), and movement abnormalities. As mentioned above, affected infants typically appear to develop normally (with the exception of hypotonia) until about six months of age, when they may seem to have generalized weakness and be unable to hold up their heads. Family members have described the latter feature as "limber neck." Due to low muscle tone, weakness, severely reduced motor development, and/or other factors, affected children have delays in learning to walk, may walk with great difficulty, or may not develop the ability to walk. Associated findings may include underdevelopment (hypoplasia) and wasting (atrophy) of various skeletal (voluntary) muscles; an impaired ability to coordinate certain voluntary movements (ataxia); weakness and stiffness of the legs (spastic paraplegia) with associated hyperreflexia and involuntary, rapid, repeated contractions and relaxations of the legs (clonus); involuntary, relatively slow, writhing movements (athetoid movements); and/or other movement abnormalities.

As noted earlier, infants and children with the disorder are also affected by severe mental retardation and delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation). In addition, affected children may have difficulty forming and articulating words (dysarthria). As a result, some children may be unable to speak or their speech may be extremely difficult to understand.

As adults, affected individuals may have generalized muscular wasting (atrophy), permanent fixation of multiple small and large joints in various fixed postures (joint contractures) and/or decreased reflex reactions (hyporeflexia).

Individuals with Allan-Herndon syndrome may also have unusual craniofacial features and/or additional skeletal abnormalities. The head is usually of normal size but may be abnormally narrow at the temples (bitemporal narrowing). In addition, the face may appear abnormally long (elongated) and thin with large, poorly developed ears. In some cases, Allan-Herndon syndrome may also be associated with abnormal side-to-side curvature of the spine (scoliosis); depression of the breastbone ("funnel chest" or pectus excavatum); and/or foot defects.
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Allan-Herndon syndrome is thought to be inherited as an X-linked recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off"’ and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son.

As mentioned above, in females who carry a single copy of a disease gene for an X-linked recessive trait (heterozygous carriers), disease traits on the X chromosome may essentially be "masked" by the normal gene on the other X chromosome. More specifically, because only one functioning X chromosome is required in males and females, one of the X chromosomes in each cell of a female is essentially "turned off," usually in a random pattern (random X chromosome inactivation). Theoretically, if the X chromosome with the gene mutation is activated in some cells, female carriers may manifest certain, typically more variable or mild features of the disorder. However, the medical literature has not reported cases in which female carriers for Allan-Herndon syndrome have developed symptoms of the disorder.

The defective gene responsible for Allan-Herndon syndrome is thought to be located on the long arm of chromosome X (Xq21), within a region that has been linked to several X-linked mental retardation disease entities (Xq12-q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p13" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. For example, "Xq12" refers to band 12 on the long arm of chromosome X.
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Allan-Herndon Syndrome is an extremely rare inherited disorder that is fully expressed in males only. Thirty-seven cases involving males from two separate families (kindreds) have been reported in the medical literature. Of these cases, 29 occurred in one family during a period of seven generations.

Symptoms of the following disorders may be similar to those of Allan-Herndon syndrome. Comparisons may be useful for a differential diagnosis:

Angelman syndrome is an extremely rare genetic disorder characterized by severe mental retardation; a delay in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); an impaired ability to coordinate voluntary movements (ataxia); periods of unprovoked laughter; absence of speech; and/or unusual facial features. Affected children may also have seizures and/or abnormally exaggerated reflexes (hyperreflexia). In addition, children with the disorder may have an abnormally small, broad head (microbrachycephaly). Most cases of Angelman syndrome appear to occur spontaneously. (For more information on this disorder, choose "Angelman" as your search term in the Rare Disease Database.)

Juberg-Marsidi syndrome is an extremely rare genetic disorder that is apparent at birth (congenital) or during the first few weeks of life (neonatal period). Most affected children have severe mental retardation; delays in reaching developmental milestones (e.g., crawling, etc.); muscle weakness (hypotonia); and/or delayed bone growth as well as growth retardation, resulting in short stature. Affected infants may also have abnormalities of the craniofacial region, such as an abnormally small head (microcephaly); a flat, depressed nasal bridge; eye (ocular) abnormalities; and/or, in some cases, additional physical abnormalities. The range and severity of symptoms may vary from case to case. Juberg-Marsidi syndrome is inherited as an X-linked recessive trait. (For more information on this disorder, choose "Juberg Marsidi" as your search term in the Rare Disease Database.)

X-linked mental retardation, Renpenning type is an extremely rare inherited disorder that is characterized by moderate to severe mental retardation. Other findings may include an abnormally small head (microcephaly), short stature, and/or small testes. Individuals with this disorder may tend to use repetitive speech and have aggressive behavior. X-linked mental retardation, Renpenning type is thought to be inherited as an X-linked recessive trait.

MASA syndrome is an extremely rare genetic disorder. The acronym MASA stands for (M)ental retardation, (A)phasia (diminished ability to communicate by speech, writing, and/or signs), (S)huffling gait, and (A)dducted (abnormally turned toward the body) thumbs. Other findings may include spasticity, exaggerated reflexes of certain tendons in the legs, abnormal curvature of the spine, and/or mild short stature. In addition, some children may have an abnormally small head (microcephaly). MASA syndrome is thought to be inherited as an X-linked recessive trait.

There are additional congenital disorders that may be characterized by X-linked mental retardation and occur in association with movement abnormalities, psychomotor retardation, and/or other features similar to those associated with Allan-Herndon syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of Allan-Herndon syndrome may be suspected in infants with diminished muscle tone (hypotonia) with poor head control that causes the head to droop (limber neck). Although hypotonia and muscle weakness may be obvious during early infancy, other symptoms associated with Allan-Herndon syndrome (e.g., athetoid movements, spastic paraplegia, etc.) may not become apparent until late infancy. Therefore, the disorder may not be diagnosed until childhood, based upon a thorough clinical evaluation, a detailed patient history, and specialized tests.

For example, abnormal reflexes, impaired ability to coordinate voluntary movements (ataxia), and/or spastic paraplegia may become obvious as an affected child develops. Mental retardation is present at birth but may not be detected until the child is old enough to respond to clinical testing. Clinical evaluation should be conducted early in development and on a continuing basis to help determine the extent of mental retardation and to ensure that appropriate steps are taken to help affected individuals reach their potential.

Treatment
The treatment of Allan-Herndon syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, neurologists, specialists who assess and treat skeletal abnormalities (orthopedists), speech-language pathologists, physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Specific therapies for the treatment of Allan-Herndon syndrome are symptomatic and supportive. Affected individuals who have scoliosis may be treated with orthopedic braces, physical therapy, and/or other orthopedic measures. When abnormal depression of the breastbone (pectus excavatum) is present, corrective surgery may be recommended in some cases.

Early intervention is important to ensure that children with Allan-Herndon syndrome reach their potential. Special services that may be beneficial include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:9/12/95. Last Update:9/12/1995. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?309600.

TEXTBOOKS
Bialer MG. Allan-Herndon-Dudley Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:149.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:1793-94, 1798.

JOURNAL ARTICLES
Colleaux L, et al. Localisation of two candidate genes for mental retardation using a YAC physical map of the Xq21.1-21.2 subbands. J Med Genet. 1996;33:353-57.

May M, et al. Molecular analysis of four males with mental retardation and deletions of Xq21 places the putative MR region in Xq21.1 between DXS233 and CHM. Hum Molec Genet. 1995;4:1465-66.

Bialer MG, et al. Allan-Herndon-Dudley syndrome: clinical and linkage studies on a second family. Am J Hum Genet. 1992;43:491-97.

Epting S, et al. Genetic linkage analysis places locus DXS250 between locus DXYS1 and locus DXS3 in Xq21.3. Cytogenet Cell Genet. 1992;60:112-13.

Stevenson RE, et al. Allan-Herndon syndrome. I. Clinical studies. Am J Hum Genet. 1990;47:446-53.

Schwartz CE, et al. Allan-Herndon syndrome. II. Linkage to DNA markers in Xq21. Am J Hum Genet. 1990;47:454-58.

Davis JG, et al. A new X-linked recessive mental retardation syndrome with progressive spastic quadriparesis [abstract]. Am J Hum Genet Suppl. 1981;33:75A.

Allan W, et al. Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly. Am J Ment Defic. 1944;48:325-34.