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Autosomal recessive distal spinal muscular atrophy 1(SIANRF; SMARD1; DSMA1; DHMN6; HMNR1)

MedGen UID:
388083
Concept ID:
C1858517
Disease or Syndrome
Synonyms: HMN VI; NEURONOPATHY, DISTAL HEREDITARY MOTOR, HARDING TYPE VI; Neuronopathy, distal hereditary motor, type VI; Neuronopathy, severe infantile axonal, with respiratory failure; NEUROPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 1; Severe infantile axonal neuropathy with respiratory failure; Spinal muscular atrophy with respiratory distress 1; SPINAL MUSCULAR ATROPHY, DIAPHRAGMATIC
SNOMED CT: Distal spinal muscular atrophy type 1 (711483003); Distal hereditary motor neuronopathy type VI (711483003); Severe infantile axonal neuropathy with respiratory failure (711483003); Spinal muscular atrophy with respiratory distress type 1 (711483003); Spinal muscular atrophy with respiratory distress (711483003); Autosomal recessive distal spinal muscular atrophy 1 (711483003); Diaphragmatic spinal muscular atrophy (711483003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): IGHMBP2 (11q13.3)
 
Monarch Initiative: MONDO:0011436
OMIM®: 604320
Orphanet: ORPHA98920

Definition

Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); HMNR10 (620542), caused by mutation in the VRK1 gene (602168); and HMNR11 (620854), caused by mutation in the RTN2 gene (603183). [from OMIM]

Additional description

From MedlinePlus Genetics
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).  https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy-with-respiratory-distress-type-1

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Clubfoot
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).
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Degeneration of anterior horn cells
MedGen UID:
375215
Concept ID:
C1843505
Finding
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
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.
Spinal muscular atrophy
MedGen UID:
7755
Concept ID:
C0026847
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.
Camptodactyly of finger
MedGen UID:
98041
Concept ID:
C0409348
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Diaphragmatic weakness
MedGen UID:
101067
Concept ID:
C0521532
Finding
A decrease in the strength of the diaphragm.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Denervation of the diaphragm
MedGen UID:
346925
Concept ID:
C1858529
Finding
Interruption of the innervation of the diaphragm.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
EMG: neuropathic changes
MedGen UID:
867363
Concept ID:
C4021727
Finding
The presence of characteristic findings of denervation on electromyography (fibrillations, positive sharp waves, and giant motor unit potentials).
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Inspiratory stridor
MedGen UID:
146165
Concept ID:
C0677600
Sign or Symptom
Inspiratory stridor is a high pitched sound upon inspiration that is generally related to laryngeal abnormalities.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Ventilator dependence with inability to wean
MedGen UID:
870643
Concept ID:
C4025097
Finding
Weak cry
MedGen UID:
65892
Concept ID:
C0234860
Finding
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
The birth of a baby of less than 37 weeks of gestational age.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.

Professional guidelines

PubMed

Perego MGL, Galli N, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S
Cell Mol Life Sci 2020 Sep;77(17):3351-3367. Epub 2020 Mar 2 doi: 10.1007/s00018-020-03492-0. PMID: 32123965Free PMC Article
Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, Zlotogora J, Shohat M
Genet Test 2008 Mar;12(1):53-6. doi: 10.1089/gte.2007.0030. PMID: 18298318

Recent clinical studies

Etiology

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
Wagner JD, Huang L, Tetreault M, Majewski J, Boycott KM, Bulman DE; Care4Rare Canada Consortium, Dyment DA, McMillan HJ
Neuromuscul Disord 2015 Oct;25(10):794-9. Epub 2015 Aug 5 doi: 10.1016/j.nmd.2015.07.017. PMID: 26298607

Diagnosis

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
Yuan JH, Hashiguchi A, Yoshimura A, Yaguchi H, Tsuzaki K, Ikeda A, Wada-Isoe K, Ando M, Nakamura T, Higuchi Y, Hiramatsu Y, Okamoto Y, Takashima H
J Hum Genet 2017 Jun;62(6):599-604. Epub 2017 Mar 9 doi: 10.1038/jhg.2017.15. PMID: 28202949
San Millan B, Fernandez JM, Navarro C, Reparaz A, Teijeira S
Clin Neuropathol 2016 Mar-Apr;35(2):58-65. doi: 10.5414/NP300902. PMID: 26709713Free PMC Article
Porro F, Rinchetti P, Magri F, Riboldi G, Nizzardo M, Simone C, Zanetta C, Faravelli I, Corti S
J Neurol Sci 2014 Nov 15;346(1-2):35-42. Epub 2014 Sep 16 doi: 10.1016/j.jns.2014.09.010. PMID: 25248952
Jędrzejowska M, Madej-Pilarczyk A, Fidziańska A, Mierzewska H, Pronicka E, Obersztyn E, Gos M, Pronicki M, Kmieć T, Migdał M, Mierzewska-Schmidt M, Walczak-Wojtkowska I, Konopka E, Hausmanowa-Petrusewicz I
Eur J Paediatr Neurol 2014 Mar;18(2):183-92. Epub 2013 Dec 15 doi: 10.1016/j.ejpn.2013.11.006. PMID: 24388491

Therapy

Shababi M, Feng Z, Villalon E, Sibigtroth CM, Osman EY, Miller MR, Williams-Simon PA, Lombardi A, Sass TH, Atkinson AK, Garcia ML, Ko CP, Lorson CL
Mol Ther 2016 May;24(5):855-66. Epub 2016 Feb 10 doi: 10.1038/mt.2016.33. PMID: 26860981Free PMC Article
Vanoli F, Rinchetti P, Porro F, Parente V, Corti S
J Cell Mol Med 2015 Sep;19(9):2058-66. Epub 2015 Jun 20 doi: 10.1111/jcmm.12606. PMID: 26095024Free PMC Article

Prognosis

Pekuz S, Güzin Y, Sarıtaş S, Kırbıyık Ö, Ünalp A, Yılmaz Ü
Turk J Pediatr 2022;64(2):364-374. doi: 10.24953/turkjped.2020.2012. PMID: 35611426
Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S
J Cell Mol Med 2020 Jan;24(2):1169-1178. Epub 2019 Dec 4 doi: 10.1111/jcmm.14874. PMID: 31802621Free PMC Article
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
Nandhagopal R, Meftah D, Al-Kalbani S, Scott P
Eur J Neurol 2018 Feb;25(2):395-403. Epub 2017 Dec 12 doi: 10.1111/ene.13519. PMID: 29115704
Ikeda A, Yamashita S, Tsuyusaki Y, Tanaka M, Tanaka Y, Hashiguchi A, Takashima H, Goto T
Brain Dev 2018 Feb;40(2):155-158. Epub 2017 Sep 9 doi: 10.1016/j.braindev.2017.08.004. PMID: 28899595

Clinical prediction guides

Prusty AB, Hirmer A, Sierra-Delgado JA, Huber H, Guenther UP, Schlosser A, Dybkov O, Yildirim E, Urlaub H, Meyer KC, Jablonka S, Erhard F, Fischer U
Cell Rep 2024 Feb 27;43(2):113802. Epub 2024 Feb 17 doi: 10.1016/j.celrep.2024.113802. PMID: 38368610
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
Han C, Mai J, Tian T, He Y, Liao J, Wen F, Yi X, Yang Y
Brain Dev 2015 May;37(5):542-5. Epub 2014 Oct 1 doi: 10.1016/j.braindev.2014.09.004. PMID: 25280635
Jędrzejowska M, Madej-Pilarczyk A, Fidziańska A, Mierzewska H, Pronicka E, Obersztyn E, Gos M, Pronicki M, Kmieć T, Migdał M, Mierzewska-Schmidt M, Walczak-Wojtkowska I, Konopka E, Hausmanowa-Petrusewicz I
Eur J Paediatr Neurol 2014 Mar;18(2):183-92. Epub 2013 Dec 15 doi: 10.1016/j.ejpn.2013.11.006. PMID: 24388491
Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hübner C, Schuelke M, von Au K
Pediatrics 2012 Jan;129(1):e148-56. Epub 2011 Dec 12 doi: 10.1542/peds.2011-0544. PMID: 22157136

Recent systematic reviews

Porro F, Rinchetti P, Magri F, Riboldi G, Nizzardo M, Simone C, Zanetta C, Faravelli I, Corti S
J Neurol Sci 2014 Nov 15;346(1-2):35-42. Epub 2014 Sep 16 doi: 10.1016/j.jns.2014.09.010. PMID: 25248952

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