Definition of Amaurotic familial idiocy

Amaurotic familial idiocy:
An outdated term for Tay-Sachs disease (TSD) which is concisely defined by OMIM (Online Mendelian Inheritance in Man) as "an autosomal recessive, progressive neurodegenerative disorder, which in the classic infantile form, is usually fatal by age 2 or 3 years, results from deficiency of the enzyme hexosaminidase A. " "Autosomal" points to the gene for TSD residing on a nonsex (autosomal) chromosome (namely, chromosome15q23-q24). "Recessive" indicates a person with 2 copies of the gene has TSD whereas someone with 1 copy is a carrier in normal health. TSD worsens, with time, as the central nervous system progressively deteriorates. The "classic" ("textbook") type of TSD has its insidious onset in infancy. The child with TSD usually develops normally for the first few months of life. An exaggerated startle reaction may first be noted. Head control is lost by 6-8 months of age. The infant cannot roll over or sit up. Spasticity and rigidity develop. Excessive drooling and convulsions become evident. Blindness and head enlargement set in by the second year. "Fatal by age 2 or 3 years" today would be modified to "fatal by age 5." After age 2, total constant nursing care is needed. Death is due usually to cachexia (wasting away) or aspiration pneumonia initiated by food going down "the wrong way" into the lungs. TSD is due to deficiency of an enzyme (a protein needed to catalyze a specific chemical reaction within the body). Lack of the enzyme which results in failure to process a lipid (a fat) which accumulates and is deposited in the brain and other tissues, to their detriment. The enzyme is called hexosaminidase-A (hex-A) and the lipid that is deposited is called GM2-ganglioside TSD is a model of a fatal metabolic disease that occurs primarily within a well-defined subpopulation. It is one of several genetic diseases found more often in persons of Jewish origin. (Other Jewish genetic diseases include Gaucher disease, Niemann-Pick disease, Bloom syndrome, and factor XI deficiency). The frequency of TSD is much higher in Ashkenazi Jews (of European origin) than in other groups of Jews. (In the U.S., 95% of Jews are Ashkenazi and are at risk for TSD). TSD occurs more rarely, in non-Jews. Knowledge of the biochemical basis TSD has permitted screening programs for carrier detection and prenatal diagnosis of TSD. There are forms of TSD with somewhat more hex-A and hence later onset, termed juvenile TSD and adult TSH. Alternative names for TSD itself are type 1 GM2-gangliosidosis, B variant GM2-gangliosidosis, hexosaminidase A deficiency, hex-A deficiency. TSD is named for the English physician Waren Tay (1843-1927) and the New York neurologist Bernard (Barney) Sachs (1858-1944). Tay in 1881 studied an infant with progressive neurological impairment and described "symmetrical changes in the yellow spot in each eye", the "cherry-red spots" characteristic of TSD. Sachs saw a child In 1887 and the child's sister in 1898 with the cherry-red spots and "arrested cerebral development" and in 1910 he demonstrated the presence of accumulated lipid in the brain and retina.

Alkaptonuria: A genetic metabolic disorder due to deficiency of the enzyme homogentisic acid (HGA) dioxygenase. Deficiency of this enzyme leads to the three cardinal features of alkaptonuria --the presence of homogentisic acid in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis.
The presence of HGA in the urine causes it to turn black upon standing when exposed to air. (Alkaptonuria was easily diagnosed among the nomadic Bedouin peoples because people with the disease left a characteristic dark spot in the sand marking the spot where they had urinated).
The ochronosis is due to the accumulation of a bluish-black pigment in connective tissues that darkly discolors them. Ochronosis occurs only after 30 years.
The pigment also accumulates in the cartilage of the joints and results in early-onset osteoarthritis. The arthritis often begins in the third decade of life when the patient is in their twenties.
Other less common features of the alkaptonuria include pigment deposition (aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation), renal stones, and prostate stones.
The diagnosis of alkaptonuria is based upon the detection of excess HGA in the urine by gas chromatography and mass spectrometry analysis. Alkaptonuria results from mutations in the gene called HGD which encodes the enzyme homogentisic acid dioxygenase. This gene has been mapped to chromosome 3 in the region of bands 3q21-q23.
More than 40 mutations in the HGD gene have been identified in people with alkaptonuria. Many of these mutations change single amino acids in the homogentisate oxidase protein. For example, a substitution of the amino acid valine for methionine at position 368 (also written as Met368Val) is the most common HGD mutation in European populations. Mutations in the HGD gene probably inactivate the enzyme by changing its structure.
Alkaptonuria is inherited in an autosomal recessive manner. The brothers and sisters of someone with alkaptonuria have a 25% chance of also being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not being a carrier. Prenatal testing is feasible.
Alkaptonuria enjoys the historic distinction of being one of the
conditions for which autosomal recessive inheritance was first proposed. This prescient proposal was made in 1902 by the English physician Archibald Garrod, later Sir Archibald. In a series of brilliant lectures in 1908 Garrod set forth the charter group of what he called "inborn errors of metabolism." The 4 conditions he labeled as inborn errors were albinism, cystinuria, pentosuria and, of course,
alkaptonuria.

Definition of ADAMTS2

ADAMTS2: A gene that encodes a metalloproteinase enzyme. This enzyme is responsible for processing type I, type II, and type V procollagen proteins. Procollagens are the precursors of collagens, the proteins that add strength and support to many body tissues. Specifically, this enzyme clips a short chain of amino acids off of one end of the procollagen. The clipping step is necessary for proper assembly and function of collagen molecules.
Mutations in the ADAMTS2 gene have been identified in patients with Ehlers-Danlos syndrome, dermatosparaxis type. These mutations greatly reduce the production of the enzyme made by ADAMTS2. Procollagen cannot be processed correctly without this enzyme. As a result, type I collagen fibrils are not assembled properly; they appear ribbon-like and disorganized under the microscope. Cross-links, or chemical interactions, between collagen fibrils are also affected. These defects weaken connective tissue, particularly in the skin, which causes the symptoms of the disorder.
The ADAMTS2 gene is located on the long (q) arm of chromosome 5 at the end (terminal) of the arm. ADAMTS2 stands for A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 2.