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Spinal muscular atrophy, distal, autosomal recessive, 6(HMNR6)

MedGen UID:
1823974
Concept ID:
C5774201
Disease or Syndrome
Synonyms: HMNR6; NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 6; NEUROPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 6
 
Gene (location): REEP1 (2p11.2)
 
Monarch Initiative: MONDO:0859279
OMIM®: 620011

Definition

Autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6) is a neuromuscular disorder characterized by onset of distal muscle weakness in early infancy. Affected individuals often present at birth with distal joint contractures or foot deformities and show delayed motor development, often with inability to walk or frequent falls. Hypo- or hyperreflexia may be observed; limb muscle atrophy may also be present. Patients often show respiratory distress or diaphragmatic palsy. Electrophysiologic studies are consistent with a peripheral motor neuropathy without sensory involvement (Maroofian et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive distal HMN, see HMNR1 (604320). [from OMIM]

Clinical features

From HPO
Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Wrist drop
MedGen UID:
533950
Concept ID:
C0231666
Finding
A condition in which the affected individual cannot extend the wrist, which hangs flaccidly.
Absent Achilles reflex
MedGen UID:
108240
Concept ID:
C0558845
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
Plantar flexion contracture
MedGen UID:
349991
Concept ID:
C1861239
Finding
A type of contracture in which the plantar flexion muscles are contracted.
Foot dorsiflexor weakness
MedGen UID:
356163
Concept ID:
C1866141
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Peripheral axonal neuropathy
MedGen UID:
266071
Concept ID:
C1263857
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Craniofacial dystonia
MedGen UID:
868612
Concept ID:
C4023011
Disease or Syndrome
A form of focal dystonia affecting the face and especially the jaw that is induced by the act of speaking. It is an involuntary contraction of the masticatory muscles, resulting in dysarthria or dysphagia.
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital failure of muscular development of part or all of one or both hemidiaphragms, resulting in superior displacement of abdominal viscera and altered lung development.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Distal arthrogryposis
MedGen UID:
120512
Concept ID:
C0265213
Disease or Syndrome
An inherited primary limb malformation disorder characterized by congenital contractures of two or more different body areas and without primary neurologic and/or muscle disease that affects limb function.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Skeletal muscle atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding
Fiber type grouping
MedGen UID:
478824
Concept ID:
C3277194
Finding
An abnormal distribution of muscle fiber types in muscle tissue. Human skeletal muscle contains at least two fiber types recognizable by histochemical techniques. In transverse sections of normal skeletal muscle, type 1 and type 2 fibers are distributed in a random fashion. Grouping of fibers of the same type can be seen in certain peripheral neuropathies, thought to be due to reinnervation of denervated muscle fibers by sprouting axons. With grouping, motor units enlarge. The fibers of a motor unit, which are normally scattered, come to lie adjacent to one another. Histochemical examination shows groups of muscle fibers of the same histochemical type.
Arthrogryposis-like hand anomaly
MedGen UID:
870719
Concept ID:
C4025173
Congenital Abnormality
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
Paradoxical respiration
MedGen UID:
534076
Concept ID:
C0231852
Sign or Symptom
Breathing movements in which the chest wall moves in on inspiration and out on expiration, in reverse of the normal movements. It may be seen in children with respiratory distress of any cause, which leads to indrawing of the intercostal spaces during inspiration. Patients with chronic airways obstruction also show indrawing of the lower ribs during inspiration, due to the distorted action of a depressed and flattened diaphragm. Crush injuries of the chest, with fractured ribs and sternum, can lead to a severe degree of paradoxical breathing.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Recurrent acute respiratory tract infection
MedGen UID:
488972
Concept ID:
C1442786
Finding
A history of repeated acute infections of the upper or lower respiratory tract.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).

Professional guidelines

PubMed

Łusakowska A, Wójcik A, Frączek A, Aragon-Gawińska K, Potulska-Chromik A, Baranowski P, Nowak R, Rosiak G, Milczarek K, Konecki D, Gierlak-Wójcicka Z, Burlewicz M, Kostera-Pruszczyk A
Orphanet J Rare Dis 2023 Aug 4;18(1):230. doi: 10.1186/s13023-023-02769-4. PMID: 37542300Free PMC Article
Calder AN, Androphy EJ, Hodgetts KJ
J Med Chem 2016 Nov 23;59(22):10067-10083. Epub 2016 Aug 16 doi: 10.1021/acs.jmedchem.6b00670. PMID: 27490705Free PMC Article
Mesfin A, Sponseller PD, Leet AI
J Am Acad Orthop Surg 2012 Jun;20(6):393-401. doi: 10.5435/JAAOS-20-06-393. PMID: 22661569

Recent clinical studies

Etiology

Mirea A, Leanca MC, Onose G, Sporea C, Padure L, Shelby ES, Dima V, Daia C
Front Biosci (Landmark Ed) 2022 Jun 6;27(6):179. doi: 10.31083/j.fbl2706179. PMID: 35748255
Waldrop MA, Karingada C, Storey MA, Powers B, Iammarino MA, Miller NF, Alfano LN, Noritz G, Rossman I, Ginsberg M, Mosher KA, Broomall E, Goldstein J, Bass N, Lowes LP, Tsao CY, Mendell JR, Connolly AM
Pediatrics 2020 Sep;146(3) doi: 10.1542/peds.2020-0729. PMID: 32843442
Islander G
Paediatr Anaesth 2013 Sep;23(9):804-16. Epub 2013 Apr 19 doi: 10.1111/pan.12159. PMID: 23601145
D'Amico A, Mercuri E, Tiziano FD, Bertini E
Orphanet J Rare Dis 2011 Nov 2;6:71. doi: 10.1186/1750-1172-6-71. PMID: 22047105Free PMC Article
Rudnik-Schöneborn S, Zerres K, Ignatius J, Rietschel M
J Neurol 1992 Jan;239(1):26-30. doi: 10.1007/BF00839207. PMID: 1541965

Diagnosis

Mirea A, Leanca MC, Onose G, Sporea C, Padure L, Shelby ES, Dima V, Daia C
Front Biosci (Landmark Ed) 2022 Jun 6;27(6):179. doi: 10.31083/j.fbl2706179. PMID: 35748255
Ross LF, Kwon JM
Neoreviews 2019 Aug;20(8):e437-e451. doi: 10.1542/neo.20-8-e437. PMID: 31371553
Islander G
Paediatr Anaesth 2013 Sep;23(9):804-16. Epub 2013 Apr 19 doi: 10.1111/pan.12159. PMID: 23601145
Mesfin A, Sponseller PD, Leet AI
J Am Acad Orthop Surg 2012 Jun;20(6):393-401. doi: 10.5435/JAAOS-20-06-393. PMID: 22661569
D'Amico A, Mercuri E, Tiziano FD, Bertini E
Orphanet J Rare Dis 2011 Nov 2;6:71. doi: 10.1186/1750-1172-6-71. PMID: 22047105Free PMC Article

Therapy

Łusakowska A, Wójcik A, Frączek A, Aragon-Gawińska K, Potulska-Chromik A, Baranowski P, Nowak R, Rosiak G, Milczarek K, Konecki D, Gierlak-Wójcicka Z, Burlewicz M, Kostera-Pruszczyk A
Orphanet J Rare Dis 2023 Aug 4;18(1):230. doi: 10.1186/s13023-023-02769-4. PMID: 37542300Free PMC Article
Chiriboga CA
Paediatr Drugs 2022 Nov;24(6):585-602. Epub 2022 Aug 27 doi: 10.1007/s40272-022-00529-8. PMID: 36028610
Mirea A, Leanca MC, Onose G, Sporea C, Padure L, Shelby ES, Dima V, Daia C
Front Biosci (Landmark Ed) 2022 Jun 6;27(6):179. doi: 10.31083/j.fbl2706179. PMID: 35748255
Waldrop MA, Karingada C, Storey MA, Powers B, Iammarino MA, Miller NF, Alfano LN, Noritz G, Rossman I, Ginsberg M, Mosher KA, Broomall E, Goldstein J, Bass N, Lowes LP, Tsao CY, Mendell JR, Connolly AM
Pediatrics 2020 Sep;146(3) doi: 10.1542/peds.2020-0729. PMID: 32843442
Prior TW
Curr Opin Pediatr 2010 Dec;22(6):696-702. doi: 10.1097/MOP.0b013e32833f3046. PMID: 20829691

Prognosis

Chiriboga CA
Paediatr Drugs 2022 Nov;24(6):585-602. Epub 2022 Aug 27 doi: 10.1007/s40272-022-00529-8. PMID: 36028610
Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C
Neuromuscul Disord 2019 Feb;29(2):114-126. Epub 2018 Oct 31 doi: 10.1016/j.nmd.2018.10.002. PMID: 30598237
D'Amico A, Mercuri E, Tiziano FD, Bertini E
Orphanet J Rare Dis 2011 Nov 2;6:71. doi: 10.1186/1750-1172-6-71. PMID: 22047105Free PMC Article
Wirth B
Hum Mutat 2000;15(3):228-37. doi: 10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9. PMID: 10679938
Rudnik-Schöneborn S, Zerres K, Ignatius J, Rietschel M
J Neurol 1992 Jan;239(1):26-30. doi: 10.1007/BF00839207. PMID: 1541965

Clinical prediction guides

Łusakowska A, Wójcik A, Frączek A, Aragon-Gawińska K, Potulska-Chromik A, Baranowski P, Nowak R, Rosiak G, Milczarek K, Konecki D, Gierlak-Wójcicka Z, Burlewicz M, Kostera-Pruszczyk A
Orphanet J Rare Dis 2023 Aug 4;18(1):230. doi: 10.1186/s13023-023-02769-4. PMID: 37542300Free PMC Article
Chiriboga CA
Paediatr Drugs 2022 Nov;24(6):585-602. Epub 2022 Aug 27 doi: 10.1007/s40272-022-00529-8. PMID: 36028610
Mirea A, Leanca MC, Onose G, Sporea C, Padure L, Shelby ES, Dima V, Daia C
Front Biosci (Landmark Ed) 2022 Jun 6;27(6):179. doi: 10.31083/j.fbl2706179. PMID: 35748255
Frongia AL, Natera-de Benito D, Ortez C, Alarcón M, Borrás A, Medina J, Vigo M, Padrós N, Moya O, Armas J, Carrera-García L, Expósito-Escudero J, Cuadras D, Bernal S, Martorell L, Colomer J, Nascimento A
Neuromuscul Disord 2019 Jul;29(7):517-524. Epub 2019 Apr 18 doi: 10.1016/j.nmd.2019.04.003. PMID: 31201046
Wirth B
Hum Mutat 2000;15(3):228-37. doi: 10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9. PMID: 10679938

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