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PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome(NEDRIHF)

MedGen UID:
863794
Concept ID:
C4015357
Disease or Syndrome
Synonyms: NEDRIHF; NEURODEVELOPMENTAL DISORDER WITH NEONATAL RESPIRATORY INSUFFICIENCY, HYPOTONIA, AND FEEDING DIFFICULTIES
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Unknown inheritance
MedGen UID:
989040
Concept ID:
CN307042
Finding
Source: Orphanet
Hereditary clinical entity whose mode of inheritance is unknown.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): PURA (5q31.3)
 
Monarch Initiative: MONDO:0018580
OMIM®: 616158
Orphanet: ORPHA438213

Disease characteristics

Excerpted from the GeneReview: PURA-Related Neurodevelopmental Disorders
PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset issues can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common. [from GeneReviews]
Authors:
Margot RF Reijnders  |  Richard J Leventer  |  Bo Hoon Lee, et. al.   view full author information

Additional descriptions

From OMIM
Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties (NEDRIHF) is characterized by severe hypotonia at birth associated with respiratory difficulties, including apnea and hypoventilation, and feeding difficulties. Many infants require ventilatory support or feeding tubes. Affected patients have global developmental delay, often never achieving walking or speech, although the severity can be variable. Additional common features may include seizures, exaggerated startle reflex, abnormal movements, and dysmorphic facial features. Brain imaging often shows hypomyelination and parenchymal atrophy. A subset of patients may have systemic features, such as cardiac defects, scoliosis, endocrine anomalies, constipation, or cryptorchidism (summary by Reijnders et al., 2018).  http://www.omim.org/entry/616158
From MedlinePlus Genetics
PURA syndrome is a condition characterized by intellectual disability and delayed development of speech and motor skills, such as walking. Expressive language skills (vocabulary and the production of speech) are generally more severely affected than receptive language skills (the ability to understand speech), and most affected individuals are unable to speak. People with PURA syndrome may learn to walk later than their peers; many are never able to walk. In infancy, affected infants have very weak muscle tone (hypotonia) and feeding difficulties. Problems with swallowing (dysphagia) can last throughout life. In addition, affected infants can be excessively sleepy (hypersomnolent), have a low body temperature (hypothermia), and have short pauses in breathing (apnea) or episodes of abnormally slow breathing (hypoventilation). These breathing problems usually go away after age 1.

Recurrent seizures (epilepsy) are also common in PURA syndrome. Seizures usually begin before age 5 with uncontrolled muscle jerks (myoclonus). Other types of seizures can develop, such as generalized tonic-clonic seizures, which involve loss of consciousness, muscle rigidity, and convulsions. In people with PURA syndrome, seizures are often difficult to control.

Other features in people with PURA syndrome can include abnormalities of the heart, eyes, urogenital tract, gastrointestinal tract, and skeleton. Some affected individuals have symptoms of a hormonal problem, such as early sexual development (precocious puberty) or low levels of vitamin D (which is a hormone).  https://medlineplus.gov/genetics/condition/pura-syndrome
From MedlinePlus Genetics
5q31.3 microdeletion syndrome is a condition characterized by severely delayed development of speech and motor skills, such as walking. Beginning in infancy, affected individuals also have weak muscle tone (hypotonia), feeding difficulties, and breathing problems. Breathing problems and difficulty swallowing (dysphagia) can be life-threatening.

5q31.3 microdeletion syndrome is also characterized by distinctive facial features. Such features include a narrow forehead, widely spaced eyes (hypertelorism), an open mouth with an upper lip that points outward (called a tented lip), a high arch in the roof of the mouth (high-arched palate), a small lower jaw (micrognathia), and a lack of facial expression. Some of these features, such as an open mouth with a tented lip and an expressionless face, are thought to be due to hypotonia.

Recurrent seizures (epilepsy) and seizure-like episodes (which can include muscle jerking, twitching, and stiffening), are common in 5q31.3 microdeletion syndrome. Many individuals with 5q31.3 microdeletion syndrome have brain abnormalities, several of which are caused by reduced production of myelin or delayed maturation of myelin. Myelin is the protective covering that insulates nerves and ensures the rapid transmission of nerve impulses.  https://medlineplus.gov/genetics/condition/5q313-microdeletion-syndrome

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Broad-based gait
MedGen UID:
167799
Concept ID:
C0856863
Finding
An abnormal gait pattern in which persons stand and walk with their feet spaced widely apart. This is often a component of cerebellar ataxia.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
CNS hypomyelination
MedGen UID:
892446
Concept ID:
C4025616
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
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.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Open mouth
MedGen UID:
116104
Concept ID:
C0240379
Finding
A facial appearance characterized by a permanently or nearly permanently opened mouth.
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).
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Tented upper lip vermilion
MedGen UID:
326574
Concept ID:
C1839767
Finding
Triangular appearance of the oral aperture with the apex in the midpoint of the upper vermilion and the lower vermilion forming the base.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Long palpebral fissure
MedGen UID:
340300
Concept ID:
C1849340
Finding
Distance between medial and lateral canthi is more than two standard deviations above the mean for age (objective); or, apparently increased length of the palpebral fissures.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Esotropia
MedGen UID:
4550
Concept ID:
C0014877
Disease or Syndrome
A form of strabismus with one or both eyes turned inward ('crossed') to a relatively severe degree, usually defined as 10 diopters or more.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome

Recent clinical studies

Etiology

Choi SA, Lee HS, Park TJ, Park S, Ko YJ, Kim SY, Lim BC, Kim KJ, Chae JH
Brain Dev 2021 Oct;43(9):912-918. Epub 2021 Jun 8 doi: 10.1016/j.braindev.2021.05.009. PMID: 34116881

Diagnosis

Qashqari H, McNiven V, Gonorazky H, Mendoza-Londono R, Hassan A, Kulkarni T, Amburgey K, Dowling JJ
Neuromuscul Disord 2022 Oct;32(10):842-844. Epub 2022 Sep 22 doi: 10.1016/j.nmd.2022.09.007. PMID: 36210261
Choi SA, Lee HS, Park TJ, Park S, Ko YJ, Kim SY, Lim BC, Kim KJ, Chae JH
Brain Dev 2021 Oct;43(9):912-918. Epub 2021 Jun 8 doi: 10.1016/j.braindev.2021.05.009. PMID: 34116881

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