Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.

Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and a discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).

SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by Bertini et al., 2000). Genetic Heterogeneity of X-linked Spinocerebellar Ataxia X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3 (301790), SCAX4 (301840), and SCAX5 (300703). SCAX6 (301310) is caused by mutation in the ABCB7 gene (300135).

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is caused by a defect in vitamin D 25-hydroxylation (Molin et al., 2017). The major function of vitamin D is to maintain calcium and phosphate levels in the normal range to support metabolic functions, neuromuscular transmission, and bone mineralization. Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (summary by Liberman and Marx, 2001). Rickets can occur because of inadequate dietary intake or sun exposure or because of genetic disorders. Vitamin D3 (cholecalciferol) is taken in the diet or synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. For vitamin D to be active, it needs to be converted to its active form, 1,25-dihydroxyvitamin D3. Vitamin D is transported in the blood by the vitamin D binding protein (DBP; 139200) to the liver, where vitamin D 25-hydroxylase (CYP2R1; 608713) is the key enzyme for 25-hydroxylation. Vitamin D 25(OH)D3, the major circulating form of vitamin D, is then transported to the kidney, where 25(OH)D3 is hydroxylated at the position of carbon 1 of the A ring, resulting in the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (summary by Christakos et al., 2010).

A very rare pure form of spastic paraplegia with characteristics of onset in infancy of lower limb spasticity associated with gait disturbances, scissor gait, tiptoe walking, clonus and increased deep tendon reflexes. Mild upper limb involvement may occasionally also be associated.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).

Spinocerebellar ataxia-29 (SCA29) is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Permanent neonatal diabetes mellitus-3 (PNDM3) is characterized by the onset of mild to severe hyperglycemia within the first months of life, and requires lifelong therapy (summary by Babenko et al., 2006). Some patients also have neurologic features, including developmental delay and epilepsy (Proks et al., 2006; Babenko et al., 2006). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND. For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (606176).

Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Amyotrophic lateral sclerosis-28 (ALS28) is an autosomal dominant neurodegenerative disorder characterized by adult onset of slowly progressive limb muscle weakness and atrophy resulting in gait difficulties, loss of ambulation, and distal upper limb weakness. Facial involvement is rare, but some patients may have respiratory insufficiency. EMG and muscle biopsy show active and chronic denervation. Patient-derived motor neurons show accumulation of TDP43 (605078) and toxic intranuclear RNA accumulation (Kume et al., 2023). For discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).