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Hyperphenylalaninemia due to DNAJC12 deficiency(HPANBH4)

MedGen UID:
1391882
Concept ID:
C4479270
Disease or Syndrome
Synonym: Hyperphenylalaninemia, mild, non-bh4-deficient
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): DNAJC12 (10q21.3)
 
Monarch Initiative: MONDO:0044304
OMIM®: 617384
Orphanet: ORPHA508523

Definition

Mild non-BH4-deficient hyperphenylalaninemia (HPANBH4) is an autosomal recessive disorder characterized by increased serum phenylalanine (HPA) usually detected by newborn screening and associated with highly variable neurologic defects, including movement abnormalities, such as dystonia, and variably impaired intellectual development. Laboratory analysis shows dopamine and serotonin deficiencies in the cerebrospinal fluid, and normal tetrahydrobiopterin (BH4) metabolism. Evidence suggests that treatment with BH4 and neurotransmitter precursors can lead to clinical improvement or even prevent the neurologic defects if started in infancy (summary by Anikster et al., 2017). The phenotype is highly variable: some patients may present with later onset of juvenile or young adult nonprogressive dopa-responsive parkinsonism reminiscent of early-onset Parkinson disease (168600). These patients benefit from treatment with L-dopa (summary by Straniero et al., 2017). In a review of HPA, Blau et al. (2018) noted that molecular screening for DNAJC12 mutations should be mandatory in patients in whom deficiencies of PAH (612349) and BH4 metabolism have been excluded. [from OMIM]

Clinical features

From HPO
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Oculogyric crisis
MedGen UID:
43221
Concept ID:
C0085637
Pathologic Function
An acute dystonic reaction with blepharospasm, periorbital twitches, and protracted fixed staring episodes. There may be a maximal upward deviation of the eyes in the sustained fashion. Oculogyric crisis can be triggered by a number of factors including neuroleptic medications.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
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.
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.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperphenylalaninemia due to DNAJC12 deficiency

Professional guidelines

PubMed

Gallego D, Leal F, Gámez A, Castro M, Navarrete R, Sanchez-Lijarcio O, Vitoria I, Bueno-Delgado M, Belanger-Quintana A, Morais A, Pedrón-Giner C, García I, Campistol J, Artuch R, Alcaide C, Cornejo V, Gil D, Yahyaoui R, Desviat LR, Ugarte M, Martínez A, Pérez B
Hum Mutat 2020 Jul;41(7):1329-1338. Epub 2020 Apr 30 doi: 10.1002/humu.24026. PMID: 32333439

Recent clinical studies

Therapy

Porta F, Neirotti A, Spada M
Neurol Sci 2023 Jun;44(6):2167-2172. Epub 2023 Mar 10 doi: 10.1007/s10072-023-06733-9. PMID: 36897462
Çıkı K, Yıldız Y, Yücel Yılmaz D, Pektaş E, Tokatlı A, Özgül RK, Sivri HS, Dursun A
Metab Brain Dis 2021 Aug;36(6):1405-1410. Epub 2021 May 20 doi: 10.1007/s11011-021-00753-0. PMID: 34014443
Straniero L, Guella I, Cilia R, Parkkinen L, Rimoldi V, Young A, Asselta R, Soldà G, Sossi V, Stoessl AJ, Priori A, Nishioka K, Hattori N, Follett J, Rajput A, Blau N, Pezzoli G, Farrer MJ, Goldwurm S, Rajput AH, Duga S
Ann Neurol 2017 Oct;82(4):640-646. Epub 2017 Oct 11 doi: 10.1002/ana.25048. PMID: 28892570

Prognosis

Wang L, Ma D, Sun Y, Wang Y, Zeng H, Liu G, Zhang J, Xu Z
Gene 2023 Jun 15;869:147397. Epub 2023 Mar 28 doi: 10.1016/j.gene.2023.147397. PMID: 36990253

Clinical prediction guides

Martínez-Pizarro A, Picó S, López-Márquez A, Rodriguez-López C, Montalvo E, Alvarez M, Castro M, Ramón-Maiques S, Pérez B, Lucas JJ, Richard E, Desviat LR
Hum Mol Genet 2024 Jun 5;33(12):1074-1089. doi: 10.1093/hmg/ddae051. PMID: 38520741Free PMC Article
Wong RSH, Mohammad S, Parayil Sankaran B, Junek R, Kim WT, Wotton T, Devanapalli B, Bandodkar S, Balasubramaniam S
Brain Dev 2023 Oct;45(9):523-531. Epub 2023 May 6 doi: 10.1016/j.braindev.2023.04.004. PMID: 37156708
Wang L, Ma D, Sun Y, Wang Y, Zeng H, Liu G, Zhang J, Xu Z
Gene 2023 Jun 15;869:147397. Epub 2023 Mar 28 doi: 10.1016/j.gene.2023.147397. PMID: 36990253
Porta F, Neirotti A, Spada M
Neurol Sci 2023 Jun;44(6):2167-2172. Epub 2023 Mar 10 doi: 10.1007/s10072-023-06733-9. PMID: 36897462

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