Wilson disease is a disorder of copper metabolism that, when untreated, can present with hepatic, neurologic, or psychiatric disturbances – or a combination of these – in individuals ages three years to older than 70 years. Manifestations in untreated individuals vary among and within families. Liver disease can include recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmune-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations can include dysarthria, movement disorders (tremors, involuntary movements, chorea, choreoathetosis), dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement), dysautonomia, seizures, sleep disorders, or insomnia. Psychiatric disturbances can include depression, bipolar disorder / bipolar spectrum disorder, neurotic behaviors, personality changes, or psychosis. Other multisystem involvement can include the eye (Kayser-Fleischer rings), hemolytic anemia, the kidneys, the endocrine glands, and the heart.

Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase (ALP). Biallelic ALPL pathogenic variants often result in severe hypophosphatasia that can result in stillbirth without mineralized bone, while heterozygous ALPL pathogenic variants are more likely to manifest as modest, mild, or even asymptomatic disease. Regardless of the number of ALPL pathogenic variants, many individuals with hypophosphatasia suffer from pain, disability, and reduced quality of life. Variability of clinical manifestations is common in both childhood and adult forms of hypophosphatasia and even occurs within affected families. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features. Perinatal (severe): Characterized by restrictive lung disease, respiratory failure, vitamin B6-dependent seizures, hypercalcemia with high morbidity, and mortality Perinatal (benign): Prenatal skeletal manifestations that slowly resolve into one of the milder forms Infantile: Onset between birth and age six months of clinical features of rickets without elevated serum ALP activity Severe childhood (juvenile): Variable presenting features progressing to rickets Mild childhood: Present later in childhood without rachitic disease, low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots Adult: Characterized by osteomalacia and stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Adults with hypophosphatasia may also have significant bone pain and pronounced non-skeletal disease, with muscle weakness, dental problems, and reduced quality of life. Odontohypophosphatasia: Characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations

Gitelman syndrome (GTLMNS) is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis (summary by Glaudemans et al., 2012). Gitelman syndrome is sometimes referred to as a mild variant of classic Bartter syndrome (607364). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

Mucopolysaccharidosis type IX (MPS9) is a rare progressive lysosomal storage disorder caused by the deficiency of the enzyme hyaluronoglucosaminidase-1, which degrades hyaluronan (summary by Imundo et al., 2011).

Any familial hypocalciuric hypercalcemia in which the cause of the disease is a mutation in the AP2S1 gene.

Autosomal dominant renal hypomagnesium wasting (HOMG2) is characterized by hypomagnesemia due to renal magnesium loss and is associated with hypocalciuria. Patients may have convulsions and muscle cramps, but they may also be asymptomatic except for the development of chondrocalcinosis at an adult age (summary by Knoers, 2009 and de Baaij et al., 2015). For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014.

Familial hypocalciuric hypercalcemia type II (HHC2) is an autosomal dominant disorder characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion and normal circulating parathyroid hormone concentrations in most patients. Patients are generally asymptomatic (summary by Nesbit et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980).

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.