IGHMBP2 Gene

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited condition that causes muscle weakness and respiratory failure typically beginning in infancy. Early features of this condition are difficult and noisy breathing, especially when inhaling; a weak cry; problems feeding; and recurrent episodes of pneumonia. Typically between the ages of 6 weeks and 6 months, infants with this condition will experience a sudden inability to breathe due to paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm). Normally, the diaphragm contracts and moves downward during inhalation to allow the lungs to expand. With diaphragm paralysis, affected individuals require life-long support with a machine to help them breathe (mechanical ventilation). Rarely, children with SMARD1 develop signs or symptoms of the disorder later in childhood.

Soon after respiratory failure occurs, individuals with SMARD1 develop muscle weakness in their distal muscles. These are the muscles farther from the center of the body, such as muscles in the hands and feet. The weakness soon spreads to all muscles; however, within 2 years, the muscle weakness typically stops getting worse. Some individuals may retain a low level of muscle function, while others lose all ability to move their muscles. Muscle weakness severely impairs motor development, such as sitting, standing, and walking. Some affected children develop an abnormal side-to-side and back-to-front curvature of the spine (scoliosis and kyphosis, often called kyphoscoliosis when they occur together). After approximately the first year of life, individuals with SMARD1 may lose their deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.

Other features of SMARD1 can include reduced pain sensitivity, excessive sweating (hyperhidrosis), loss of bladder and bowel control, and an irregular heartbeat (arrhythmia).

Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

Charcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.

Typically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.

Affected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.

There are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.

Sometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome.