Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives

Figures & data

Box 1 Genes Associated with Inherited Metabolic Diseases Involving Epilepsy or Seizures as a Symptom

Disorders of amino acid metabolism: AASS, ACAD8, ACADSB, ACY1, ADK, ALDH18A1, ALDH4A1, AMT, ARG1, ASL, ASNS, ASPA, ASS1, AUH, BCKDHA, BCKDHB, BCKDK, CBS, CPS1, DBT, ECHS1, ETHE1, GAD1, GCDH, GLDC, GLS, GLUD1, GLUL, GPT2, HIBCH, IVD, MCCC1, MCCC2, MLYCD, MMUT, MTR, NAGS, NAT8L, OTC, PAH, PCCA, PCCB, PHGDH, PRODH, PSAT1, PSPH, PYCR2, SLC1A1, SLC1A2, SLC1A3, SLC1A4, SLC25A13, SLC25A15, SLC6A1, SLC6A19, SQOR, SUOX.

Disorders of peptide and amine metabolism: GSS, ODC1, SMS, XPNPEP3.

Disorders of carbohydrate metabolism: ALDOB, EPM2A, FBP1, GCK, GK, GLYCTK, GYS1, GYS2, HK1, NHLRC1, PC, PCK1, PFKM, PGK1, PRKAG2, RPIA, SLC17A5, SLC2A1, SLC45A1.

Disorders of fatty acid and ketone body metabolism: ACADM, ACADS, ACAT1, CPT1A, CPT2, ETFA, ETFB, ETFDH, HADH, HADHA, HADHB, HMGCL, HMGCS2, SLC16A1, SLC25A20.

Disorders of energy substrate metabolism: ACO2, DLAT, DLD, FH, GAMT, GATM, IDH2, IDH3A, MDH2, MPC1, PDHA1, PDHB, PDHX, PDP1, SLC13A5, SLC6A8, SUCLA2, SUCLG1.

MT-DNA related disorders: MT-ATP6, MT-ATP8, MT-CO1, MT-CYB, MT-ND1, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-TC, MT-TF, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TN, MT-TP, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TV, MT-TW.

Nuclear-encoded disorders of oxidative phosphorylation: APOPT1, ATP5F1A, ATP5F1D, ATP5MD, BCS1L, COX10, COX14, COX15, COX20, COX4I1, COX6B1, COX8A, CYC1, FASTKD2, FOXRED1, HCCS, LRPPRC, LYRM7, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA2, NDUFA4, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB11, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NUBPL, PET100, SCO1, SCO2, SDHA, SDHAF1, SDHD, SURF1, TACO1, TIMMDC1, TMEM70, UQCC2.

Disorders of mitochondrial cofactor biosynthesis: BOLA3, COQ2, COQ4, COQ5, COQ6, COQ8A, COQ8B, COQ9, IBA57, ISCA1, LIAS, LIPT2, NFS1, PDSS2.

Disorders of mitochondrial DNA maintenance and replication: DGUOK, MPV17, POLG, POLG2, RRM2B, SAMHD1, TK2, TWNK.

Disorders of mitochondrial gene expression: AARS2, CARS2, DARS2, EARS2, FARS2, GFM1, GFM2, GTPBP3, GUF1, HSD17B10, IARS2, KARS1, LARS2, MRM2, MRPL12, MRPS22, MRPS34, MTFMT, MTO1, NARS2, PARS2, PNPT1, QRSL1, RARS2, RMND1, TRIT1, TRNT1, TSFM, TUFM, VARS2, WARS2.

Other disorders of mitochondrial function: AFG3L2, AIFM1, ATAD3A, CLPB, CLPP, DNAJC19, FBXL4, GOT2, HSPD1, HTRA2, LONP1, MDH1, MICU1, MIPEP, PMPCB, PPA2, PTRH2, RTN4IP1, SLC25A1, SLC25A10, SLC25A12, SLC25A22, TIMM50, TXN2.

Disorders of metabolite repair and proofreading: ACSF3, D2HGDH, L2HGDH.

Disorders of lipid metabolism: ABCD1, ACOX1, ALDH3A2, AMACR, BSCL2, CERS1, CERS2, CHKB, CYP27A1, DDHD2, DEGS1, DHCR24, DHCR7, EBP, ELOVL4, FA2H, FAR1, FDFT1, FIG4, HSD17B4, HSD3B7, INPP5K, LBR, LSS, MBOAT7, MFSD2A, MVK, NSDHL, OCRL, PCYT2, PEX5, PEX7, PI4K2A, PIK3CA, PIK3R2, PLA2G6, PLCB1, PTEN, SGPL1, SYNJ1.

Disorders of lipoprotein metabolism: VLDLR.

Disorders of nucleobase, nucleotide and nucleic acid metabolism: AARS1, ADA2, ADARB1, ADAT3, ADSL, AIMP1, AIMP2, AMPD2, ATIC, CAD, CARS1, CLP1, DALRD3, DPYD, DPYS, EMG1, EPRS1, FARSB, FTSJ1, IARS1, IFIH1, ITPA, KARS1, LAGE3, LARS1, NARS1, NSUN2, NT5C3A, OSGEP, POLR3A, PRPS1, PUS3, QARS1, RARS1, RNASEH2A, RNASEH2B, RNASEH2C, RNASET2, RPL10, SARS1, SNORD118, TP53RK, TPRKB, TREX1, TRMT1, TRMT10A, TSEN15, TSEN2, TSEN34, TSEN54, UBTF, UPB1, VARS1, WDR4, YARS1.

Disorders of tetrapyrrole metabolism: ALAD, CPOX, HMBS, PPOX, UGT1A1.

Congenital disorders of glycosylation: ALG1, ALG11, ALG12, ALG13, ALG14, ALG2, ALG3, ALG6, ALG9, ATP6AP1, ATP6AP2, ATP6V0A2, ATP6V1A, B3GALNT2, B3GLCT, B4GAT1, CCDC115, DHDDS, DOLK, DPAGT1, DPM1, DPM2, DPM3, EXT2, EXTL3, FCSK, FKRP, FKTN, FUT8, GMPPA, GMPPB, GNE, GPAA1, HS6ST2, LARGE1, MAN1B1, MGAT2, MOGS, MPDU1, NANS, NDST1, NGLY1, NUS1, OSTC, PGAP1, PGAP2, PGAP3, PGM1, PIGB, PIGG, PIGH, PIGK, PIGL, PIGM, PIGN, PIGO, PIGP, PIGQ, PIGS, PIGT, PIGU, PIGV, PIGW, PIGY, PMM2, POMGNT1, POMK, POMT1, POMT2, RFT1, SLC35A1, SLC35A2, SLC35A3, SLC35C1, SRD5A3, SSR4, ST3GAL3, ST3GAL5, STT3A, STT3B, TMEM165, UGDH, UGP2.

Disorders of organelle biogenesis, dynamics and interactions: AP1S2, AP3B2, AP3D1, AP4B1, AP4E1, AP4M1, AP4S1, ARCN1, ARFGEF2, BCAP31, COG2, COG4, COG5, COG6, COG7, COG8, COL4A3BP, DNM1L, GOSR2, LYST, MFF, MICOS13, MYO5A, PEX1, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, PEX2, PEX26, PEX3, PEX5, PEX6, PISD, PNPLA8, RAB18, RAB27A, RAB3GAP1, RUBCN, SCYL2, SERAC1, SLC25A46, SPATA5, STAT2, STX11, STXBP2, TANGO2, TRAK1, TRAPPC11, TRAPPC12, TRAPPC2L, TRAPPC4, TRAPPC6B, TRAPPC9, VPS11, VPS13A, VPS13B, VPS4A, YIF1B.

Disorders of complex molecule degradation: AGA, ARSA, ASAH1, ASAH1, ATP13A2, CLN3, CLN5, CLN6, CLN8, CTSA, CTSD, CTSF, DNAJC5, EPG5, FUCA1, GALC, GBA, GLA, GLB1, GM2A, GNS, GRN, HEXA, HEXB, HGSNAT, IDS, KCTD7, MANBA, MFSD8, NAGA, NAGLU, NEU1, NPC1, NPC2, PPT1, PSAP, SCARB2, SGSH, SMPD4, SNX14, SPG11, SUMF1, TECPR2, TPP1, WDR45.

Disorders of vitamin and cofactor metabolism: ALDH7A1, ALPL, BTD, DHFR, FOLR1, GCH1, GPHN, HCFC1, HLCS, LMBRD1, MMAA, MMACHC, MMADHC, MADHC, MOCS1, MOCS2, MTHFD1, MTHFR, MTHFS, MTRR, NADK2, NAXD, NAXE, NNT, PANK2, PLPBP, PNPO, PTS, QDPR, SLC19A2, SLC19A3, SLC25A19, SLC25A42, SLC46A1, SLC5A6, SPR, TPK1.

Disorders of trace elements and metals: ATP7A, ATP7B, CCS, FTL, SEPSECS, SLC33A1, SLC39A8.

Neurotransmitter disorders: ABAT, ALDH5A1, ATAD1, CLTC, DBH, DNAJC6, DNM1, DYNC1H1, GABBR2, GABRA1, GABRB1, GABRB2, GABRB3, GABRG2, GLRA1, GLRB, GRIA2, GRIA3, GRIA4, GRIN1, GRIN2A, GRIN2B, GRIN2D, GRM1, GRM1, IL1RAPL1, KIF1A, KIF5A, KIF5C, PRRT2, SLC18A2, SLC6A5, SNAP25, SNAP29, STX1B, STXBP1, SV2A, SYN1, TBC1D24, TH, VAMP2.

Endocrine metabolic disorders: ABCC8, AKT2, HNF1B, KCNJ11, MC2R.

Note: the classification of IMDs presented according to Ferreira et al¹ http://www.icimd.org/; http://www.iembase.org/.

Box 2 The Goals of Multidisciplinary Care in IMD Patients with Epilepsy or Seizures

● Address the needs of patients with complex care needs and their families in a holistic, comprehensive, family-centered way. ● Find the right balance between highly-specialized and locally provided services in the individual patient care plans. ● Ensure proper care coordination and communication between families and caregivers through the involvement of (specialist) nurse coordinators or case managers. ● Ensure proper management of care transitions by giving special consideration to all life stage-related (eg, transition from pediatric to adult services, pregnancy and perinatal care) and disease stage-related (eg, transition to palliative services) transitions. ● Ensure proper management of emergencies (including those related to metabolic decompensation and/or epilepsy-related emergencies). ● Provide multipronged empowerment of patients and families, including provision of required information, involvement into common decision-making, education, support for self-management, liaison with peer support groups and emotional/ psychological support. ● Exploit international collaboration (in particular ERNs) and digital technologies for accessible, cost-effective and high-quality care.

Figure 1 Care pathways for IMD patients with epilepsy or seizures.

Table 1 Multidisciplinary Teams for Care of IMD Patients with Epilepsy or Seizures

Supervision	Core Multidisciplinary Team	Extended Multidisciplinary Team
Named highly-specialized physician: • Metabolic pediatrician or specialist of adult IMDs; • Pediatric or adult neurologist/ epileptologist; • Geneticist or other specialist.	• General practitioner; • Care coordinator(s); • Laboratory specialists; • Geneticist; • Dietician; • Specialized nurse; • Intensive care specialist; • Rehabilitation specialist; • Psychologist; • Social worker; • Neuroradiologist; • Neurophysiologist; • Neurosurgeon; • Etc. according to the needs.	• Neonatologist; • Obstetrician-gynecologist; • Palliative care specialist; • Pharmacist; • Etc. according to the needs.

Ferreira CR, Rahman S, Keller M, et al. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. 2021;44(1):164–177. doi:10.1002/jimd.12348

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