Table 3.

Hereditary Disorders in the Differential Diagnosis of Hypermanganesemia with Dystonia 1

GeneDiff Dx DisorderMOIClinical Characteristics
Disorders of metal metabolism
SLC39A14 SLC39A14 deficiency (HMNDYT2)ARManganese transporter defect caused by impaired manganese uptake into liver. Affected persons present w/hypermanganesemia & rapidly progressive childhood-onset PD-DYT due to cerebral manganese deposition. Brain MRI appears the same as in HMNDYT1. Distinguishing features: absence of liver disease & polycythemia due to lack of hepatic manganese deposition (can be assessed by liver MRI)
ATP7B Wilson disease ARDisorder of copper metabolism that can present w/hepatic, neurologic, or psychiatric disturbances (or a combination) from age 3 yrs to >50 yrs. Neurologic presentations incl mvmt disorders or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement).
Monogenic Parkinson disease 1 & hereditary disorders in the DiffDx of Parkinson disease
ATP13A2
DNAJC6
FBXO7
PODXL
SLC6A3
SYNJ1 		Juvenile-onset Parkinson disease (PD) 3ARAge of onset of PD generally <20 yrs. Clinical presentation often incl addl signs incl dystonia, spasticity, & dementia.
GBA1 (GBA)
LRRK2
PARK7
PINK1
PRKN
SNCA
VPS13C
VPS35		Early-onset adult & late-onset adult Parkinson disease 2AD
AR		PD is characterized by rest tremor, muscle rigidity, slowed movement, & often postural instability. Onset is typically unilateral & may incl other abnormal movements (e.g., postural or action tremor & limb dystonia). Common assoc non-motor findings incl insomnia, depression, anxiety, REM sleep behavior disorder, fatigue, constipation, dysautonomia, & hyposmia. As part of a prodromal phase, non-motor features may predate formal diagnosis of PD by yrs.
ATN1 DRPLA ADProgressive disorder of ataxia, myoclonus, epilepsy, & progressive intellectual deterioration in children; ataxia, choreoathetosis, & dementia or character changes in adults. Clinical presentation varies w/age of onset. Cardinal features in adults: ataxia, choreoathetosis, dementia; in children: progressive intellectual deterioration, behavioral changes, myoclonus, epilepsy
HTT Huntington disease ADProgressive disorder of motor, cognitive, & psychiatric disturbances. Mean age of onset 35-44 yrs. Affected persons may present w/neurologic manifestations or psychiatric changes.
Hereditary dystonia (selected examples of early-onset dystonia &/or dopa-responsive dystonia)
GCH1 GTP cyclohydrolase 1-deficient dopa-responsive dystonia AD
AR		Childhood-onset dystonia & dramatic & sustained response to low doses of oral administration of levodopa. Most common presenting findings: posturing or irregular tremor of a leg or arm (due to dystonic muscle contractions)
KMT2B KMT2B-related dystonia ADComplex childhood-onset mvmt disorder. Typically presents w/progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia w/prominent cervical, cranial, & laryngeal involvement
SPR Sepiapterin reductase deficiency ARRare cause of partially dopa-responsive childhood-onset dystonia characterized by axial hypotonia, motor & speech delay, weakness, & oculogyric crises; symptoms show diurnal fluctuation & sleep benefit.
TH TH-deficient dopa-responsive dystonia (See Tyrosine Hydroxylase Deficiency.)ARAge of onset 12 mos-2 yrs. Initial manifestations: typically lower-limb dystonia &/or difficulty in walking. Diurnal fluctuation of symptoms may be present.
THAP1 DYT-THAP1ADAlthough some phenotypic overlap w/DYT-TOR1A is observed, the onset of DYT-THAP1 is later (mean age 19 yrs) & cranial involvement is more prominent esp in muscles of the tongue, larynx, & face; dysphonia is a predominant feature.
TOR1A DYT1 early-onset isolated dystonia ADTypically presents in childhood or adolescence & only on occasion in adulthood. Most common presenting findings: posturing or irregular tremor of a leg or arm (due to dystonic muscle contractions)
Neurodegenerative diseases assoc w/dystonia
ATP13A2
C19orf12
COASY
CP
DCAF17
FA2H
FTL
PANK2
PLA2G6
WDR45 		Neurodegeneration with brain iron accumulation disorders AR
AD
XL 3		Characterized by abnormal accumulation of iron in basal ganglia. Generalized cerebral atrophy & cerebellar atrophy are frequently observed. Hallmark clinical manifestations: progressive dystonia & dysarthria, spasticity, parkinsonism, neuropsychiatric abnormalities, optic atrophy or retinal degeneration. Although cognitive decline occurs in some genetic types, more often cognition is relatively spared. Onset from infancy to adulthood.
DLAT
DLD
PDHA1
PDHB
PDHX
PDP1
PDK3 		Primary pyruvate dehydrogenase complex deficiency (PDCD)XL
AR 4		Most commonly manifests as syndrome of neurologic signs (congenital microcephaly, hypotonia, epilepsy, &/or ataxia), abnormal brain imaging (dysgenesis of corpus callosum, Leigh syndrome), & metabolic abnormalities (↑ plasma pyruvate, lactic acidemia, &/or metabolic acidosis). DD is nearly universal. Mean age of diagnosis of primary PDCD typically~45 mos (median ~20 mos).
GBA1 (GBA)Gaucher disease (GD)ARGD types 2 & 3 are characterized by presence of primary neurologic disease. Disease w/onset age <2 yrs, limited psychomotor development, & rapidly progressive course w/death by age 1-2 yrs is classified as GD type 2. Persons w/GD type 3 may have onset <2 yrs, but often more slowly progressive course, w/survival into 3rd-4th decade.
NPC1
NPC2 		Niemann-Pick disease type C ARPrincipal manifestations are age dependent. Perinatal period & infancy: features are predominantly visceral, w/hepatosplenomegaly, jaundice, & (in some) pulmonary infiltrates. Late infancy onward: presentation dominated by neurologic manifestations. The youngest children may present w/hypotonia & DD, w/subsequent emergence of ataxia, dysarthria, dysphagia, &, in some, epileptic seizures, dystonia, & gelastic cataplexy.
Hereditary spastic paraplegia (selected examples of more commonly involved genes)
ATL1
KIF1A
REEP1
SPAST 		Autosomal dominant HSP 5ADThe predominant signs & symptoms of HSP are lower-extremity weakness & spasticity. When symptoms begin in very early childhood, they may be non-progressive & resemble spastic diplegic cerebral palsy.
CYP7B1
SPG11
SPG7 		Autosomal recessive HSP 5AR

DD = developmental delay; DiffDx = differential diagnosis; DYT = dystonia; HSP = hereditary spastic paraplegia; HMNDYT1 = hypermanganesemia with dystonia 1; PD = Parkinson disease

1.

An estimated 5%-10% of all Parkinson disease is attributed to pathogenic variants in single genes (monogenic Parkinson disease).

2.

Early-onset adult Parkinson disease (PD) = onset at age 20-50 years. Late-onset adult PD = onset after age 50 years.

3.

Seven of the ten genetically defined types of neurodegeneration with brain iron accumulation are inherited in an autosomal recessive manner. Exceptions: neuroferritinopathy, an autosomal dominant disorder caused by a pathogenic variant in FTL; mitochondrial membrane protein-associated neurodegeneration (MPAN), an autosomal recessive or autosomal dominant disorder caused by mutation of C19orf12; and beta-propeller protein-associated neurodegeneration (BPAN), an X-linked disorder.

4.

PDHA1- and PDK3-related primary pyruvate dehydrogenase complex deficiency (PDCD) are inherited in an X-linked manner. Primary PDCD caused by pathogenic variants in DLAT, DLD, PDHB, PDHX, or PDP1 is inherited in an autosomal recessive manner.

5.

To date, more than 80 genetic types of hereditary spastic paraplegia (HSP) have been defined by genetic linkage analysis and identification of HSP-related gene variants. Autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms of HSP have been identified.

From: Hypermanganesemia with Dystonia 1

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