Amyotrophy, Hereditary Neuralgic (HNA)

What is Amyotrophy, Hereditary Neuralgic (HNA)?

This rare disease is a genetic condition that generally presents with symptoms when an affected individual reaches early adulthood.

The condition is currently believed to affect 200 families worldwide, to date.

Severe arm and shoulder pain, which can last anywhere from a few minutes to several days, is the main feature of this rare disease.

This syndrome is also known as:
Amyotrophy; Hereditary Neuralgic; With Predilection For Brachial Plexus Brachial Plexus Neuropathy; Hereditary Neuralgic amyotrophy Neuritis With Brachial Predilection; Napb Parsonage and Turner syndrome Parsonage-Turner syndrome

What gene changes cause Amyotrophy, Hereditary Neuralgic (HNA)?

Over half of all cases of the syndrome are the result of mutations in the SEPT9 gene which can be found on chromosome 17. The remaining identified cases have no specific gene yet identified responsible for causing the syndrome. It is inherited in an autosomal dominant pattern.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

What are the main symptoms of Amyotrophy, Hereditary Neuralgic (HNA)?

Severe pain in the arm and shoulder is the main symptom of the syndrome. This pain can last for days or weeks at a time and causes a wasting of the muscles which worsens with time.

The syndrome is caused by gene mutations but a number of environmental, physical and emotional factors may trigger it. These factors include stress, childbirth, excessive exercise, surgery, emotional stress, colds and infections.

Some individuals with the syndrome have some of the following distinct facial features- facial asymmetry, webbed digits, eyes positioned very closely together, a short stature and excess skin folds on the arms and neck.

Possible clinical traits/features:
Short stature, Hyporeflexia, Hypotelorism, Depressed nasal bridge, Respiratory failure, Round face, Sleep disturbance, Ptosis, Upslanted palpebral fissure, Axonal degeneration, Oral cleft, Cleft palate, Skeletal muscle atrophy, Acrocyanosis, Blepharophimosis, Arthralgia, Deeply set eye, Epicanthus, EMG abnormality, Facial asymmetry, Sprengel anomaly, Autosomal dominant inheritance, Peripheral neuropathy, Polyneuropathy, Paresthesia, Neurological speech impairment, Narrow mouth, Muscle weakness, Low-set ears

How does someone get tested for Amyotrophy, Hereditary Neuralgic (HNA)?

The initial testing for Amyotrophy, Hereditary Neuralgic syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Amyotrophy, Hereditary Neuralgic

Syndrome Overview:
Hereditary neuralgic amyotrophy (HNA) is characterized by sudden attacks of severe pain in the upper limbs followed by muscle wasting/atrophy. Some families have characteristic facial features that include hypotelorism and cleft palate. Heterozygous mutations in the SEPT9 gene cause the autosomal dominant disorder, but there is evidence of genetic heterogeneity.

Clinical Description:
Brachial plexus neuritis exists in both a sporadic (more common) and familial form, and it seems likely that only the familial form has dysmorphic features.

The neurological condition is characterized by episodes of pain, mostly in the upper arm, followed by weakness and sometimes wasting. Sensory changes coexist with the weakness, but recovery over weeks is usually full. Occasionally the lower cranial nerves are involved.

In approximately half of patients, nerves outside the brachial plexus are involved during an attack, including the lumbosacral plexus, phrenic nerve and recurrent laryngeal nerve (van Alfen et al., 2006).

In addition to muscle weakness and wasting, clinical manifestations can include vocal cord paralysis and respiratory distress.

EMG shows evidence of axonal interruption in muscles supplied by the nerves involved. SAPs and MAPs may be reduced in distal segments of clinically affected nerves. There is no evidence of a generalized neuropathic process.

The dysmorphic features include a small mouth, hypotelorism and often small, upslanting palpebral fissures. Other dysmorphic features include short stature, partial syndactyly, cleft uvula or cleft palate, and excessive skin folds on the neck and arms.

Note that Schilbach-Rott syndrome presents with a very similar facial appearance.

Differentiation from familial recurrent pressure palsy, which is inherited in the same way, can be problematic, as in some families the condition might be provoked by trauma.

In the family reported by Erikson (1974), all three affected members had a cleft palate.

Airaksinen et al., (1985) reported 13 affected members from three generations of a family and provided a good review of the literature.

Orstavik et al., (1997) reported an affected mother and son.

One patient presented with a vocal cord paralysis (To and Traquina, 1999).

Watts et al., (2002) suggest a founder effect in the American population.

Laccone et al., (2008) reported a family that was remarkable in terms of the facial dysmorphology (blepharophimosis, ptosis, upslanting, short palpebral fissures and cleft palate/uvula).

van Alfen (2011) reviewed the syndrome, differential diagnosis, associated factors and treatment. Tjoumakaris et al., (2012) also include epidemiology and MR images.

The names of Parsonage and Turner are associated with this condition.

Age of Onset:
Onset ranges from infancy to adulthood. The median age of onset is 28 years (van Alfen et al., 2006).

Specific Mutations:
This condition maps to 17q24-25 (Pellegrino et al., 1996; Stogbauer et al., 1997; Wehnert et al., 1997), but there is evidence of heterogeneity (Pellegrino et al., 1996; Stogbauer et al., 1997). The locus was refined to 17q25 (Meuleman et al., 1999).

Note above the two clinical phenotypes and the fact that the non-classic type did not map to 17q24 (van Alfen et al., 2000).

The mutated gene, SEPT9, has now been found (Kuhlenbaumer et al., 2005). Septins are implicated in the formation of the cytoskeleton, cell division and tumorigenesis.

Leshinsky-Silver et al., (2013) described six patients from a family with heterozygous R88W mutation in the SEPT9 gene. Clinical characteristics in the proband included severe inspiratory stridor, tachypnea, choking, feeding problems and paradoxical diaphragmatic movements at birth. Recurrent bilateral paralysis of the vocal cords, recurrent brachial weakness and nerve paralysis, mild hypotelorism, neck and arm skin folds, and hypotonia were additional features. Other family members exhibited relapsing-remitting episodes of pain and arm weakness without any involvement of the vocal cords or the diaphragm.

Chuk et al., (2016) reported a 5-year-old male patient with a de novo missense mutation in the SEPT9 gene and neuralgic amyotrophy in the right upper limb after an episode of gastroenteritis. He underwent treatment with intravenous immunoglobulin. Pain was diminished in six hours, and 12 months later, he had full recovery of function and muscular bulk.

* This information is courtesy of the L M D.

If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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